Macrocyclic compounds as protein kinase inhibitors

ABSTRACT

There is provided compounds of formula I, wherein R1, R 2a , R 2b , R 2c , X, Y, Z, R 3  and ring A/B have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. PI3-K, particularly class I PI3K, PIM family kinase and/or mTOR) is desired and/or required, and particularly in the treatment of cancer. The invention also relates to combinations containing such compounds.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/118,009, filed Nov. 15, 2013, which is a U.S. National Stage ofInternational Application No. PCT/GB/2012/051134, filed May 18, 2012;which, in turn, claims priority to European Patent Application No.12275024.3, filed Mar. 9, 2012 and European Patent Application No.11382158.1, filed May 19, 2011. The entire teachings of each of theaforementioned applications are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel pharmaceutically-useful compounds, whichcompounds are useful as inhibitors of protein or lipid kinases (such asinhibitors of the phosphoinositide 3′OH kinase (PI3 kinase) family,particularly the PI3K class I sub-type). The compounds may also beuseful as inhibitors of the mammalian target of rapamycin (mTOR), andmay optionally also be useful as inhibitors of a PIM family kinase (e.g.PIM-3 and, especially PIM-1). The compounds are of potential utility inthe treatment of diseases such as cancer. The invention also relates tothe use of such compounds as medicaments, to the use of such compoundsfor in vitro, in situ and in vivo diagnosis or treatment of mammaliancells (or associated pathological conditions), to pharmaceuticalcompositions containing them, and to synthetic routes for theirproduction.

BACKGROUND OF THE INVENTION

The malfunctioning of protein kinases (PKs) is the hallmark of numerousdiseases. A large share of the oncogenes and proto-oncogenes involved inhuman cancers code for PKs. The enhanced activities of PKs are alsoimplicated in many non-malignant diseases, such as benign prostatehyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis andpost-surgical stenosis and restenosis. PKs are also implicated ininflammatory conditions and in the multiplication of viruses andparasites. PKs may also play a major role in the pathogenesis anddevelopment of neurodegenerative disorders.

For a general reference to PKs malfunctioning or disregulation see, forinstance, Current Opinion in Chemical Biology 1999, 3, 459-465.

Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid andserine/threonine kinases that catalyze the phosphorylation of themembrane lipid phosphatidylinositol (PI) on the 3′-OH of the inositolring to produce phosphoinositol-3-phosphate (PIP),phosphoinositol-3,4-diphosphate (PIP₂) andphosphoinositol-3,4,5-triphosphate (PIP₃), which act as recruitmentsites for various intracellular signalling proteins, which in turn formsignalling complexes to relay extracellular signals to the cytoplasmicface of the plasma membrane. These 3′-phosphoinositide subtypes functionas second messengers in intracellular signal transduction pathways (seee.g. Trends Biochem. Sci 22 87, 267-72 (1997) by Vanhaesebroeck et al.;Chem. Rev. 101 (8), 2365-80 (2001) by Leslie et al (2001); Annu. Rev.Cell. Dev. Boil. 17, 615-75 (2001) by Katso et al; and Cell. Mol. LifeSci. 59 (5), 761-79 (2002) by Toker et al).

Multiple PI3K isoforms categorized by their catalytic subunits, theirregulation by corresponding regulatory subunits, expression patterns andsignalling specific functions (p110α, β, δ, γ) perform this enzymaticreaction (Exp. Cell. Res. 25 (1), 239-54 (1999) by Vanhaesebroeck andKatso et al., 2001, above).

The closely related isoforms p110α and β are ubiquitously expressed,while δ and γ are more specifically expressed in the haematopoietic cellsystem, smooth muscle cells, myocytes and endothelial cells (see e.g.Trends Biochem. Sci. 22 (7), 267-72 (1997) by Vanhaesebroeck et al).Their expression might also be regulated in an inducible mannerdepending on the cellular, tissue type and stimuli as well as diseasecontext. Inductibility of protein expression includes synthesis ofprotein as well as protein stabilization that is in part regulated byassociation with regulatory subunits.

Eight mammalian PI3Ks have been identified so far, including four classI PI3Ks. Class Ia includes PI3Kα, PI3Kβ and PI3Kδ. All of the class Iaenzymes are heterodimeric complexes comprising a catalytic subunit(p110α, p110β or p110δ) associated with an SH2 domain containing p85adapter subunit. Class Ia PI3Ks are activated through tyrosine kinasesignalling and are involved in cell proliferation and survival. PI3Kαand PI3Kβ have also been implicated in tumorigenesis in a variety ofhuman cancers. Thus, pharmacological inhibitors of PI3Kα and PI3Kβ areuseful for treating various types of cancer.

The potential role of PI3K over-signaling in the development of lymphoidmalignancies was initially identified in an experiment by Borlado et al.(Borlado LR, Redondo C, Alvarez B, et al. Increased phosphoinositide3-kinase activity induces a lymphoproliferative disorder and contributesto tumor generation in viva, FASEB J 2000; 14(7):895-903). In thatstudy, a mouse model with PI3K over-signaling developed infiltratinglymphoproliferative disorders as well as autoimmune disease. The PI3Kpathway plays an important role in the development of B-cellmalignancies, mainly through activation of the p110δ subunit. Inhibitionof p110δ could have a role in the management of B-cell malignancies suchas chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL),plasma cell myeloma (PCM) and Hodgkin's lymphoma (HL). (for a review,see Expert Opin Investig Drugs. 2012 January; 21(1):15-22. CAL-101: aphosphatidylinositol-3-kinase p110-delta inhibitor for the treatment oflymphoid malignancies, Castillo J J, Furman M, Winer E S).

PI3Kγ, the only member of the Class Ib PI3Ks, consists of a catalyticsubunit p110γ, which is associated with a p110 regulatory subunit. PI3Kγis regulated by G protein coupled receptors (GPCRs) via association withβγ subunits of heterotrimeric G proteins. PI3Kγ is expressed primarilyin hematopoietic cells and cardiomyocytes and is involved ininflammation and mast cell function. Thus, pharmacological inhibitors ofPI3Kγ are useful for treating a variety of inflammatory diseases,allergies and cardiovascular diseases.

These observations show that deregulation of phosphoinositol-3-kinaseand the upstream and downstream components of this signalling pathway isone of the most common deregulations associated with human cancers andproliferative diseases (see e.g. Parsons et al., Nature 436:792 (2005);Hennessey et al., Nature Rev. Drug Discovery 4: 988-1004 (2005).

The mammalian target of rapamycin (mTOR) also known as FK506 bindingprotein 12-rapamycin associated protein 1 (FRAP1) is a protein which inhumans is encoded by the FRAP1 gene. mTOR is a serine/threonine proteinkinase that regulates cell growth, cell proliferation, cell motility,cell survival, protein synthesis, and transcription. The inhibition ofmTORs are believed to be useful for treating variousdiseases/conditions, such as cancer (for example, as described in Eastonet al. (2006). “mTOR and cancer therapy”. Oncogene 25 (48): 6436-46).

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

For the treatment of cancer, targeted therapies are becoming moreimportant. That is, therapy that has the effect of interfering withspecific target molecules that are linked to tumor growth and/orcarcinogenesis. Such therapy may be more effective than currenttreatments (e.g. chemotherapy) and less harmful to normal cells (e.g.because chemotherapy has the potential to kill normal cells as well ascancerous cells). This, and also the fact that targeted therapies may beselective (i.e. it may inhibit a certain targeted molecule moreselectively as compared to other molecular targets, e.g. as describedhereinafter), may have the benefit of reducing side effects and may alsohave the benefit that certain specific cancers can be treated (alsoselectively). The latter may in turn also reduce side effects.

PIM-1 is the protooncogene activated by murine leucemia virus (ProvirusIntegration site for Moloney murine leucemia virus—MoMuLV) that inducesT-cell lymphoma [Cuypers, H. T., et. al. Cell, 1984, 37, 141-150].

The expression of the protooncogene produces a non-transmembraneserine/threonine kinase of 313 residues, including a kinase domainconsisting of 253 amino acid residues. Two isoforms are known throughalternative initiation (p44 and p33) [Saris, C. J. M. et al. EMBO J.1991, 10, 655-664].

PIM-1, PIM-2 and PIM-3 phosphorylate protein substrates that areimportant in cancer neogenesis and progression. For example, PIM-1phosphorylates inter alia p21, Bad, c-myb, Cdc 25A and eIF4B (see e.g.Quian, K. C. et al, J. Biol. Chem. 2005, 280(7), 6130-6137, andreferences cited therein).

Two PIM-1 homologs have been described [Baytel, D. Biochem. Biophys.Acta 1998, 1442, 274-285; Feldman, J. et al. J. Biol. Chem. 1998, 273,16535.16543]. PIM-2 and PIM-3 are respectively 58% and 69% identical toPIM-1 at the amino acid level. PIM-1 is mainly expressed in thymus,testis, and cells of the hematopoietic system [Mikkers, H.; Nawijn, M.;Allen, J.; Brouwers, C.; Verhoeven, E.; Jonkers, J.; Berns, Mol. Cell.Biol. 2004, 24, 6104; Bachmann, M.; Moroy, T. Int. J. Biochem. CellBiol. 2005, 37, 726-730. 6115]. PIM-1 expression is directly induced bySTAT (Signal Transducers and Activators of Transcription) transcriptionfactors, and PIM-1 expression is induced by many cytokine signallingpathways such as interleukins (IL), granulocyte-macrophage colonystimulating factor (GM-CSF), α- and γ-interferon, erythropoietin, andprolactin [Wang, Z et al. J. Vet. Sci. 2001, 2, 167-179].

PIM-1 has been implicated in lymphoma development. Induced expression ofPIM-1 and the protooncogene c-myc synergise to increase the incidence oflymphomagenesis [Breuer, M. et al. Nature 1989, 340, 61-63; van LohuizenM. et al. Cell, 1991, 65, 737-752]. PIM-1 functions in cytokinesignalling pathways and has been shown to play a role in T celldevelopment [Schmidt, T. et al. EMBO J. 1998, 17, 5349-5359; Jacobs, H.et al. JEM 1999, 190, 1059-1068]. Signalling through gp130, a subunitcommon to receptors of the IL-6 cytokine family, activates thetranscription factor STAT3 and can lead to the proliferation ofhematopioetic cells [Hirano, T. et al. Oncogene 2000, 19, 2548-2556]. Akinase-active PIM-1 appears to be essential for the gp130-mediated STAT3proliferation signal. In cooperation with the c-myc PIM-1 can promoteSTAT3-mediated cell cycle progression and antiapoptosis [Shirogane, T.et al., immunity, 1999, 11, 709-719]. PIM-1 also appears to be necessaryfor IL-3-stimulated growth in bone marrow-derived mast cells [Domen, J.et al., Blood, 1993, 82, 1445-1452] and survival of FDCP1 cells afterIL-3 withdrawal [Lilly, M. et al., Oncogene, 1999, 18, 4022-4031].

Additionally, control of cell proliferation and survival by PIM-1 may beeffected by means of its phosphorylation of the well-established cellcycle regulators cdc25 [Mochizuki, T. et al., J. Biol. Chem. 1999, 274,18659-18666] and/or p21(Cip1WAF1) [Wang Z. et al. Biochim. Biophys. Acta2002, 1593, 45-55] or phosphorylation of heterochromatin protein 1, amolecule involved in chromatin structure and transcriptional regulation[Koike, N. et al, FEBS Lett. 2000, 467, 17-21].

Mice deficient for all three PIM genes showed an impaired response tohematopoietic growth factors and demonstrated that PIM proteins arerequired for efficient proliferation of peripheral T lymphocyes. Inparticular, it was shown that PIM function is required for efficientcell cycle induction of T cells in response to synergistic T-cellreceptor and IL-2 signalling. A large number of interaction partners andsubstrates of PIM-1 have been identified, suggesting a pivotal role forPIM-1 in cell cycle control, proliferation, as well as in cell survival.

The oncogenic potential of this kinase has been first demonstrated in Eμ PIM-1 transgenic mice in which PIM-1 over-expression is targeted tothe B-cell lineage which leads to formation of B-cell tumors [vanLohuizen, M. et al.; Cell 1989, 56, 673-682. Subsequently PIM-1 has beenreported to be over-expressed in a number of prostate cancers,erythroleukemias, and several other types of human leukemias [Roh, M. etal.; Cancer Res. 2003, 63, 8079-8084; Valdman, A. et al; Prostate 2004,60, 367-371;

For example, chromosomal translocation of PIM-1 leads to overexpressionof PIM-1 in diffuse large cell lymphoma. [Akasaka, H. et al.; CancerRes. 2000, 60, 2335-2341]. Furthermore, a number of missense mutationsin PIM-1 have been reported in lymphomas of the nervous system andAIDS-induced non-Hodgkins' lymphomas that probably affect PIM-1 kinaseactivity or stability [Pasqualucci, L. et al, Nature 2001, 412, 341-346;Montesinos-Rongen, M. et al., Blood 2004, 103, 1869-1875; Gaidano, G. etal., Blood 2003, 102, 1833-184]. Thus, the strong linkage betweenreported overexpression data and the occurrence of PIM-1 mutations incancer suggests a dominant role of PIM-1 in tumorigenesis.

Several other protein kinases have been described in the literature, inwhich the activity and/or elevated activity of such protein kinases havebeen implicated in diseases such as cancer, in a similar manner toPIM-1, PIM-2 and PIM-3.

It has also been reported that PIM-1 has a role in pulmonary arteryhypertension (PAH), see the journal article by Paulin et al, “Signaltransducers and activators of transcription-3/PIM-1 axis plays acritical role in the pathogenesis of human pulmonary arterialhypertension”.

There is a constant need to provide alternative and/or more efficaciousinhibitors of protein kinases, and particularly inhibitors of PIM-1,PIM-2 and/or PIM-3. Such modulators are expected to offer alternativeand/or improved approaches for the management of medical conditionsassociated with activity and/or elevated activity of PIM-1, PIM-2 and/orPIM-3 protein kinases.

For the treatment of cancer, targeted therapies are becoming moreimportant. That is, therapy that has the effect of interfering withspecific target molecules that are linked to tumor growth and/orcarcinogenesis. Such therapy may be more effective than currenttreatments (e.g. chemotherapy) and less harmful to normal cells (e.g.because chemotherapy has the potential to kill normal cells as well ascancerous cells). This, and also the fact that targeted therapies may beselective (i.e. it may inhibit a certain targeted molecule moreselectively as compared to other molecular targets, e.g. as describedhereinafter), may have the benefit of reducing side effects and may alsohave the benefit that certain specific cancers can be treated (alsoselectively). The latter may in turn also reduce side effects.

Hence, it is a clear goal of current oncologists to develop targetedtherapies (e.g. ones that are selective). In this respect, it should bepointed out that several different molecular targets may exist that arelinked to certain diseases (e.g. cancer). However, one simply cannotpredict if a therapy (e.g. a small molecule as a therapeutic) thatinterferes with or inhibits one target molecule could inhibit adifferent molecular target (be it one that will ultimately have theeffect of treating the same disease or a different one).

International patent applications WO 2009/055418, WO 2010/108074, WO2009/040552, WO 2010/112874 and WO 2011/022439 (as well as journalarticle J Med Chem by Okseon Kim et al “Design and Synthesis ofImidazopyridine Analogues as Inhibitors of PI3K Signaling andAngiogenesis”) all disclose various compounds for use as kinaseinhibitors. However, none of these documents disclose macrocycles.

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

DISCLOSURE OF THE INVENTION

According to the invention, there is provided a compound of formula I,

wherein:

ring A and ring B represent a fused bicyclic group of any one of thefollowing formulae:

wherein

in formula IA: W^(1a) is CH, CF or N; W^(2a) is CH, CF or N; W^(3a) isCR^(4a) or N; W^(4a) is CR^(5a) or N; W^(5a) is CR^(6a) or N;

in formula IB: W^(1b) is CH, CF or N; W^(2b) is CH, CF or N; W^(3b) isCR^(4b) or N; W^(4b) is C or N; W^(5b) is CR^(6b) or N; W^(6b) is C orN; W^(7b) is C or N, and wherein when W^(3b) represents N, W^(4b) andW^(6b) represent C and W^(5b) represents C or N, then R* is hydrogen (inall other cases R* is absent);

in formula IC: W^(1c) is CH, CR^(t1), N, NR^(q1), O or S; W^(2c) is CH,CR^(t2), N, NR^(q2), O or S; W³ is C or N; W^(4c) is CR^(5c) or N;W^(5c) is CR^(6c) or N; W^(6x) is C or N;

in formula ID: W^(1d) is CH, CR^(t3), N, NR^(q3), O or S; W^(2d) is CH,CR^(t4), N, NR^(q4), O or S; W^(3d) is C or N; W^(4d) is CR^(5d) or N;W^(5d) is C or N; W^(6d) is C or N;

each R^(t1), R^(t2), R^(t3) and R^(t4) is independently selected fromhalo, C₁₋₃ alkyl (e.g. acyclic C₁₋₃ alkyl or cyclopropyl), a 3- to5-membered heterocycloalkyl group, —OR^(s1), —CN, —N(R^(s2))R^(s3),—S(O)_(w1)CH₃ or —C(O)CH₃;

w1 represents 0, 1 or 2;

each R^(s1), R^(s2) and R^(3s) independently represent hydrogen or C₁₋₂alkyl;

each R^(q1), R^(q2), R^(q3) and R^(q4) is independently selected fromC₁₋₃ alkyl (e.g. acyclic C₁₋₃ alkyl or cyclopropyl), a 3- to 5-memberedheterocycloalkyl group or —C(O)CH₃;

each R¹, R^(2a), R^(2b), R^(2c), R³, R^(4a), R^(5a), R^(6a), R^(4b),R^(6b), R^(5c), R^(6c) and R^(5d) are independently selected fromhydrogen or a substituent selected from halo, —CN, —C(O)N(R^(f1))R^(f2),—C(O)R^(f3), —N(R^(f4))R^(f5), —C(O)OR^(f6), —OR^(f7), —OC(O)—R^(f8),—S(O)_(w2)CH₃ or C₁₋₈ alkyl (e.g. acyclic C₁₋₆ alkyl or C₃₋₇ cycloalkyl)and a 3- to 8-membered heterocycloalkyl groups, which alkyl andheterocycloalkyl groups are optionally substituted by one or moresubstituents selected from ═O and E¹;

w2 represents 0, 1 or 2;

R^(f1), R^(f2), R^(f4), R^(f5) and R^(f7) independently representhydrogen or C₁₋₆ alkyl optionally substituted by one or moresubstituents selected from ═O and E²; or

R^(f1) and R^(f2) and/or R^(f4) and R^(f5) may be linked together toform a 4- to 8- (e.g. 5- to 6-) membered ring optionally substituted byone or more substituents selected from C₁₋₃ alkyl and halo;

R^(f3), R^(f6) and R^(f8) independently represent C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from ═O and E²;

X represents a direct bond, —C(R^(a))(R^(b))—, —O—, —S—, —N(R^(c))—,—N(R^(d))C(O)—, —C(O)N(R^(e))— or —N(R^(f))—C(O)—N(R^(g))—;

Y represents -arylene-, -heteroarylene- (which latter two groups areoptionally substituted by one or more substituents selected from E³),-heterocycloalkylene- or —C₁₋₁₂alkylene- (which latter two groups areoptionally substituted by one or more substituents selected from ═O andE⁴);

R^(N) represents hydrogen or C₁₋₆ alkyl optionally substituted by one ormore substituents selected from ═O and E⁵;

Z represents -(A^(x))₁₋₇- or, particularly, -(A^(x))₂₋₇-, wherein eachA^(x) independently represents —C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—,—O—, —S—, —S(O)— or —S(O)₂—;

R^(x1), R^(x2) and R^(x3) each independently represent hydrogen or asubstituent selected from E_(x);

each E_(x) independently represents halo, —C(O)R^(y1),—N(R^(y2))—C(O)—N(R^(y3))(R^(y4)), C₁₋₆ alkyl or heterocycloalkyl (bothof which latter two groups are optionally substituted by one or morehalo atoms);

R^(y1), R^(y2), R^(y3) and R^(y4) each independently represent hydrogenor C₁₋₃ alkyl optionally substituted by one or more halo atoms;

each R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) independentlyrepresent hydrogen or C₁₋₆ alkyl optionally substituted by one or morehalo atoms;

each E¹, E², E³, E⁴ and E⁵ independently represents, on each occasionwhen used herein:

(i) Q⁴;

(ii) C₁₋₁₂ alkyl or heterocycloalkyl, both of which are optionallysubstituted by one or more substituents selected from ═O and Q⁵;

any two E¹, E², E³, E⁴ and/or E⁵ groups (for example on C₁₋₁₂ alkylgroups, e.g. when they are attached to the same or adjacent carbonatoms, or, on aromatic groups, when attached to adjacent atoms), may belinked together to form a 3- to 12-membered ring, optionally containingone or more (e.g. one to three) unsaturations (preferably, doublebonds), and which ring is optionally substituted by one or moresubstituents selected from ═O and J¹;

each Q⁴ and Q⁵ independently represent, on each occasion when usedherein: halo, —CN, —N(R²⁰)R²¹, —OR²⁰, —C(═Y¹)—R²⁰, —C(═Y¹)—OR²⁰,—C(═Y¹)N(R²⁰)R²¹, —C(═Y¹)N(R²⁰)—O—R^(21a), —OC(═Y¹)—R²⁰, —OC(═Y¹)—OR²⁰,—OC(═Y¹)N(R²⁰)R²¹, —OS(O)₂OR²⁰, —OP(═Y¹)(OR²⁰)(OR²¹), —OP(OR²⁰)(OR²¹),—N(R²²)C(═Y¹)R²¹, —N(R²²)C(═Y¹)OR²¹, —N(R²²)C(═Y¹)N(R²⁰)R²¹,—NR²²S(O)₂R²⁰, —NR²²S(O)₂N(R²⁰)R²¹, —S(O)₂N(R²⁰)R²¹, —SC(═Y¹)R²⁰,—SC(═Y¹)OR²⁰, —SC(═Y¹)N(R²⁰)R²¹, —S(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂OR²⁰,C₁₋₆ alkyl or heterocycloalkyl (which latter two groups are optionallysubstituted by one or more substituents selected from ═O and J²);

each Y¹ independently represents, on each occasion when used herein, ═O,═S, ═NR²³ or ═N—CN;

each R^(21a) represents C₁₋₆ alkyl or heterocycloalkyl (which latter twogroups are optionally substituted by one or more substituents selectedfrom J⁴ and ═O);

each R²⁰, R²¹, R²² and R²³ independently represent, on each occasionwhen used herein, hydrogen, C₁₋₆ alkyl or heterocycloalkyl (which lattertwo groups are optionally substituted by one or more substituentsselected from J⁴ and ═O); or

any relevant pair of R²⁰, R²¹ and R²², may (for example, when attachedto the same atom, adjacent atom (i.e. 1,2-relationship) or to atoms thatare two atoms apart, i.e. in a 1,3-relationship) be linked together toform (e.g. along with the requisite nitrogen atom to which they may beattached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionallycontaining one or more heteroatoms (for example, in addition to thosethat may already be present, e.g. (a) heteroatom(s) selected fromoxygen, nitrogen and sulfur), optionally containing one or moreunsaturations (preferably, double bonds), and which ring is optionallysubstituted by one or more substituents selected from J⁶ and ═O;

each J¹, J², J⁴ and J⁶ independently represents, on each occasion whenused herein:

(i) Q⁷;

(ii) C₁₋₆ alkyl or heterocycloalkyl, both of which are optionallysubstituted by one or more substituents selected from ═O and Q⁸;

each Q⁷ and Q⁸ independently represents, on each occasion when usedherein:

halo, —CN, —N(R⁵⁰)R⁵¹, —OR⁵⁰, —C(═Y^(a))—R⁵⁰, —C(═Y^(a))—OR⁵⁰,—C(═Y^(a))N(R⁵⁰)R⁵¹, —N(R⁵²)C(═Y^(a))R⁵¹, —NR⁵²S(O)₂R⁵⁰,—S(O)₂N(R⁵⁰)R⁵¹, —N(R⁵²)—C(═Y^(a))—N(R⁵⁰)R⁵¹, —S(O)₂R⁵⁰, —SR⁵⁰,—S(O)R⁵⁰, C₁₋₆ alkyl (optionally substituted by one or more fluoroatoms) or heterocycloalkyl (optionally substituted by one or moresubstituents selected from halo, —OR⁶⁰ and —N(R⁶¹)R⁶²);

each Y^(a) independently represents, on each occasion when used herein,═O, ═S, ═NR⁵³ or ═N—CN;

each R⁵⁰, R⁵¹, R⁵² and R⁵³ independently represents, on each occasionwhen used herein, hydrogen or C₁₋₆ alkyl optionally substituted by oneor more substituents selected from fluoro, —OR⁶⁰ and —N(R⁶¹)R⁶²; or

any relevant pair of R⁵⁰, R⁵¹ and R⁵² may (for example when attached tothe same or adjacent atoms) be linked together to form, a 3- to8-membered ring, optionally containing one or more heteroatoms (forexample, in addition to those that may already be present, heteroatomsselected from oxygen, nitrogen and sulfur), optionally containing one ormore unsaturations (preferably, double bonds), and which ring isoptionally substituted by one or more substituents selected from ═O andC₁₋₃ alkyl;

R⁶⁰, R⁶¹ and R⁶² independently represent hydrogen or C₁₋₆ alkyloptionally substituted by one or more fluoro atoms;

or a pharmaceutically acceptable ester, amide, solvate or salt thereof,

which compounds, esters, amides, solvates and salts are referred tohereinafter as “the compounds of the invention”.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound offormula I with one or more equivalents of an appropriate acid or base,optionally in a solvent, or in a medium in which the salt is insoluble,followed by removal of said solvent, or said medium, using standardtechniques (e.g. in vacuo, by freeze-drying or by filtration). Salts mayalso be prepared by exchanging a counter-ion of a compound of theinvention in the form of a salt with another counter-ion, for exampleusing a suitable ion exchange resin.

By “pharmaceutically acceptable ester, amide, solvate or salt thereof”,we include salts of such an ester or amide, and solvates of such anester, amide or salt. For instance, pharmaceutically acceptable estersand amides such as those defined herein may be mentioned, as well aspharmaceutically acceptable solvates or salts.

Pharmaceutically acceptable esters and amides of the compounds of theinvention are also included within the scope of the invention.Pharmaceutically acceptable esters and amides of compounds of formula Imay have an appropriate group, for example an acid group, converted tothe appropriate ester or amide. For example, pharmaceutically acceptableesters (of carboxylic acids) that may be mentioned include optionallysubstituted C₁₋₆ alkyl, C₅₋₁₀ aryl and/or C₅₋₁₀ aryl-C₁₋₆ alkyl- esters.Pharmaceutically acceptable amides (of carboxylic acids) that may bementioned include those of the formula —C(O)N(R^(z1))R^(z2), in whichR^(z1) and R^(z2) independently represent optionally substituted C₁₋₆alkyl, C₅₋₁₀ aryl, or C₅₋₁₀ aryl-C₁₋₆ alkylene-. Preferably, C₁₋₆ alkylgroups that may be mentioned in the context of such pharmaceuticallyacceptable esters and amides are not cyclic, e.g. linear and/orbranched.

Preferably, specific esters and amides of compounds of the inventionthat may be mentioned include those esters and amides those mentionedherein in respect of compounds of formula I (or compounds of theinvention).

Further compounds of the invention that may be mentioned includecarbamate, carboxamido or ureido derivatives, e.g. such derivatives ofexisting amino functional groups.

For the purposes of this invention, therefore, prodrugs of compounds ofthe invention are also included within the scope of the invention.

The term “prodrug” of a relevant compound of the invention includes anycompound that, following oral or parenteral administration, ismetabolised in vivo to form that compound in anexperimentally-detectable amount, and within a predetermined time (e.g.within a dosing interval of between 6 and 24 hours (i.e. once to fourtimes daily)). For the avoidance of doubt, the term “parenteral”administration includes all forms of administration other than oraladministration.

Prodrugs of compounds of the invention may be prepared by modifyingfunctional groups present on the compound in such a way that themodifications are cleaved, in vivo when such prodrug is administered toa mammalian subject. The modifications typically are achieved bysynthesising the parent compound with a prodrug substituent. Prodrugsinclude compounds of the invention wherein a hydroxyl, amino,sulfhydryl, carboxy or carbonyl group in a compound of the invention isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxy functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. I-92, Elesevier, New York-Oxford (1985).

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. Positional isomers may also be embraced by the compounds ofthe invention. All such isomers (e.g. if a compound of the inventionincorporates a double bond or a fused ring, the cis- and trans-forms,are embraced) and mixtures thereof are included within the scope of theinvention (e.g. single positional isomers and mixtures of positionalisomers may be included within the scope of the invention).

Compounds of the invention may also exhibit tautomerism. All tautomericforms (or tautomers) and mixtures thereof are included within the scopeof the invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerisations. Valencetautomers include interconversions by reorganisation of some of thebonding electrons.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution), for example with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person.

All stereoisomers (including but not limited to diastereoisomers,enantiomers and atropisomers) and mixtures thereof (e.g. racemicmixtures) are included within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature). Allisotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention.Exemplary isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁸Cl, ¹²³I, and ¹²⁵I.Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and for substratetissue distribution assays. Tritiated (³H) and carbon-I4 (¹⁴C) isotopesare useful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances. Positronemitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positronemission tomography (PET) studies to examine substrate receptoroccupancy. Isotopically labeled compounds of the present invention cangenerally be prepared by following procedures analogous to thosedisclosed in e.g. the schemes and/or Examples hereinbelow, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming aC_(3-q)-cycloalkyl group). Such cycloalkyl groups may be monocyclic orbicyclic and may further be bridged. Further, when there is a sufficientnumber (i.e. a minimum of four) of carbon atoms, such groups may also bepart cyclic. Such alkyl groups may also be saturated or, when there is asufficient number (i.e. a minimum of two) of carbon atoms, beunsaturated (forming, for example, a C_(2-q) alkenyl or a C_(2-q)alkynyl group).

Unless otherwise stated, the term C_(1-q) alkylene (where q is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number of carbon atoms, be saturated or unsaturated (soforming, for example, an alkenylene or alkynylene linker group).However, such C_(1-q) alkylene groups are preferably not branched. Such“alkylene” groups may be appropriate linker groups that are a part ofthe macrocyclic structure of formula I. For the avoidance of doubt, anyoptional substituents on the alkylene groups are not an integral part ofthe linking moiety, i.e. when “Y” represents substituted alkylene, thenthe substituent(s) are not linked to “X” or “Z”, but are located on thealkylene moiety.

C_(3-q) cycloalkyl groups (where q is the upper limit of the range) thatmay be specifically mentioned may be monocyclic or bicyclic alkylgroups, which cycloalkyl groups may further be bridged (so forming, forexample, fused ring systems such as three fused cycloalkyl groups). Suchcycloalkyl groups may be saturated or unsaturated containing one or moredouble or triple bonds (forming for example a cycloalkenyl orcycloalkynyl group). Substituents may be attached at any point on thecycloalkyl group. Further, where there is a sufficient number (i.e. aminimum of four) such cycloalkyl groups may also be part cyclic. For theavoidance of doubt, optional substituents may also be other cyclicgroups, which may be attached via a single carbon atom common to bothrings, so forming a spiro-cycle.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

Heterocycloalkyl groups that may be mentioned include non-aromaticmonocyclic and bicyclic heterocycloalkyl groups in which at least one(e.g. one to four) of the atoms in the ring system is other than carbon(i.e. a heteroatom), and in which the total number of atoms in the ringsystem is from five to ten (between five and ten). Such heterocycloalkylgroups may also be bridged. Further, such heterocycloalkyl groups may besaturated or unsaturated containing one or more double and/or triplebonds, forming for example a C_(3-q) heterocycloalkenyl (where q is theupper limit of the range) or a C₇ heterocycloalkynyl group. C_(3-q)heterocycloalkyl groups that may be mentioned include7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl,azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl(including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl,imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl,6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl,pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyland 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl,thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl andthe like. Substituents on heterocycloalkyl groups may, whereappropriate, be located on any atom in the ring system including aheteroatom. The point of attachment of heterocycloalkyl groups may bevia any atom in the ring system including (where appropriate) aheteroatom (such as a nitrogen atom), or an atom on any fusedcarbocyclic ring that may be present as part of the ring system.Heterocycloalkyl groups may also be in the N- or S-oxidised form (i.e.those heteroatoms may be substituted with one or two ═O substituents, asappropriate). As stated herein other carbon atoms of theheterocycloalkyl groups mentioned herein may also be substituted by oneor more ═O substituents. For the avoidance of doubt, optionalsubstituents may also be other cyclic groups, which may be attached viaa single carbon atom common to both rings (so forming a Spiro cycle).

The term “-heterocycloalkylene-” refers to a heterocycloalkyl group thatis a part of a linker group. Each hyphen therefore represents the pointof attachment to the moieties to which they are attached. For instancewhen Y represents -heterocycloalkylene-, then the hyphens represent thepoint of attachment to “X” and “Z”. The point of attachment may be viaany appropriate atom (e.g. a nitrogen or carbon atom of thatheterocycloalkyl moiety). Where it is indicated that such a moiety maybe substituted, the optional substituents are not an integral part ofthe macrocycle, i.e. in the case where Y represents substituted-heterocycloalkylene-, then those substituents are not directly linkedto “X” or “Z”.

For the avoidance of doubt, the term “bicyclic” (e.g. when employed inthe context of heterocycloalkyl groups) refers to groups in which thesecond ring of a two-ring system is formed between two adjacent atoms ofthe first ring. The term “bridged” (e.g. when employed in the context ofcycloalkyl or heterocycloalkyl groups) refers to monocyclic or bicyclicgroups in which two non-adjacent atoms are linked by either an alkyleneor heteroalkylene chain (as appropriate).

Aryl groups that may be mentioned include C₆₋₁₀ aryl groups. Such groupsmay be monocyclic, bicyclic or tricyclic and have from 6 to 10 (between6 and 10) ring carbon atoms, in which at least one ring is aromatic.C₆₋₁₀ aryl groups include phenyl, naphthyl and the like, such as1,2,3,4-tetrahydronaphthyl. The point of attachment of aryl groups maybe via any atom of the ring system. However, when aryl groups arebicyclic or tricyclic, they are linked to the rest of the molecule viaan aromatic ring. For the avoidance of doubt, optional substituentsinclude those defined herein and also include ═O substituents that maybe attached to any non-aromatic rings of a polycyclic (e.g. bicyclic)aryl group (however, in an embodiment, ═O substituents are notincluded). For the avoidance of doubt, optional substituents may also beother cyclic groups, which may be, when attached to a non-aromatic ringof an aryl group, attached via a single carbon atom common to both rings(so forming a spiro-cycle).

Unless otherwise specified, the term “heteroaryl” when used hereinrefers to an aromatic group containing one or more heteroatom(s) (e.g.one to four heteroatoms) preferably selected from N, O and S. Heteroarylgroups include those which have from 5 to 10 (between 5 and 10) membersand may be monocyclic, bicyclic or tricyclic, provided that at least oneof the rings is aromatic (so forming, for example, a mono-, bi-, ortricyclic heteroaromatic group). However, when heteroaryl groups arebicyclic or tricyclic, they are linked to the rest of the molecule viaan aromatic ring. Heteroaryl groups that may be mentioned includeacridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl(including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl,benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl,benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl(including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl,benzomorpholinyl, benzoselenadiazolyl (including2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl,cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl,indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl,naphthyridinyl (including 1,6-naphthyridinyl or, preferably,1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl,phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl(including 1,2,3,4-tetrahydroisoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl),tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl,thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl,1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents onheteroaryl groups may, where appropriate, be located on any atom in thering system including a heteroatom. For the avoidance of doubt, optionalsubstituents include those defined herein and also include ═Osubstituents that may be attached to any non-aromatic rings of apolycyclic (e.g. bicyclic) heteroaryl group (but, in an embodiment, ═Osubstituents are not included). For the avoidance of doubt, optionalsubstituents may also be other cyclic groups, which may be, whenattached to a non-aromatic ring of a heteroaryl group, attached via asingle carbon atom common to both rings (so forming a spiro-cycle). Thepoint of attachment of heteroaryl groups may be via any atom in the ringsystem including (where appropriate) a heteroatom (such as a nitrogenatom), or an atom on any fused carbocyclic ring that may be present aspart of the ring system. Heteroaryl groups may also be in the N- orS-oxidised form.

The terms “-arylene-” and “-heteroarylene-” refer to aryl/heteroarylgroups that are a part of a linker group. Each hyphen thereforerepresents the point of attachment to the moieties to which they areattached. For instance when Y represents “-arylene-” and“-heteroarylene-”, then the hyphens represent the point of attachment to“X” and “Z”. The point of attachment may be via any appropriate atom(e.g. a nitrogen or carbon atom of those moieties). Where it isindicated that those moieties may be substituted, the optionalsubstituents are not an integral part of the macrocycle, i.e. in thecase where Y represents substituted -arylene- or -heteroarylene-, thenthose substituents are not directly linked to “X” or “Z”.

It may be specifically stated that the heteroaryl group is monocyclic orbicyclic. In the case where it is specified that the heteroaryl isbicyclic, then it may consist of a five-, six- or seven-memberedmonocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another afive-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroarylring).

Heteroatoms that may be mentioned include phosphorus, silicon, boronand, preferably, oxygen, nitrogen and sulphur.

Linker groups, for example as defined by X and Z are specified withhyphens (“-”s) at the respective ends, depicting the points ofattachment with the rest of the compound of formula I. For the avoidanceof doubt, in relation to the linker groups defined by Z, the firsthyphen of the linking moiety is the point at which that moiety links tothe requisite phenyl ring (bearing R² and R³ groups) and the last hyphendepicts the linking point to the Y group. Similarly, for the X linkergroup the first hyphen represents the point of attachment to the Y groupand the last hyphen represents the point of attachment to ring NB.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent. For example, in the situation in which there is morethan one Q⁴ substituent present, then those Q⁴ substituents may be thesame or different. Further, in the case where there are two Q⁴substituents present, in which one represents —OR²⁰ and the otherrepresents —C(O)—R²⁰, then those R²⁰ groups are not to be regarded asbeing interdependent.

For the avoidance of doubt, in the instance where cyclic substituents(e.g. cycloalkyl or heterocycloalkyl groups) are present on groups (suchas alkyl groups), then those cyclic substituents may be attached to thesame carbon atom, so forming for example a spiro-cyclic group.

All individual features (e.g. preferred features) mentioned herein maybe taken in isolation or in combination with any other feature(including preferred feature) mentioned herein (hence, preferredfeatures may be taken in conjunction with other preferred features, orindependently of them).

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation from e.g. a reaction mixture to a usefuldegree of purity.

For instance, it is indicated herein that A^(x) may represent variousintegers. However, certain integers may not be linked together ifunstable groups are formed, e.g. —O— may not be linked to —S—, etc. Theskilled person will appreciate the combinations that are possible, inorder for the group to be sufficiently stable and/or for the rules ofvalency to be adhered to.

For the avoidance of doubt, when a term such as “E¹ to E⁴” is employedherein, this will be understood by the skilled person to mean E¹, E², E³and E⁴, inclusively. Likewise, a term such as “R¹ to R⁶” when employedherein, will be understood by the skilled person to mean every single R¹to R⁶ group, i.e. R¹, R^(2a), R^(2b), R^(2c), R³, R^(4a), R^(5a),R^(6a), R^(4b), R^(6b), R^(5c), R^(6c) and R^(5d), inclusively.

In another embodiment of the invention, R^(N) represents hydrogen and Zrepresents -(A^(x))₂₋₇-.

In an embodiment of the invention, R^(N) represents C₁₋₃ alkyl (e.gmethyl) or, particularly, hydrogen.

In another embodiment of the invention:

R^(N) represents C₁₋₆ alkyl (e.g. C₁₋₃ alkyl) optionally substituted byone or more substituents selected from ═O and E⁵; and/or

Z represents -(A^(x))-.

Preferred compounds of the invention include those in which:

R^(4a) and R^(6a) (or, R^(4a), R^(5a) and R^(6a)) independentlyrepresent hydrogen;

in formula IA: W^(3a) is CH or N; W^(5a) is CH or N (or, W^(3a) is CH orN; W^(4a) is CH or N; W^(5a) is CH or N);

R^(6b) (or, R^(4b) and R^(6b) independently) represents hydrogen;

in formula IB: W^(3b) is CH or N (or, W^(3b) is CH or N; W^(5b) is CH orN);

R^(5c) and R^(6c) independently represent hydrogen;

in formula IC: W^(4c) is CH or N; W^(5c) is CH or N;

R^(5d) represents hydrogen;

in formula ID: W^(4d) is CH or N;

R¹ represents a substituent selected from hydrogen or, particularly,C₁₋₆ alkyl (e.g. acyclic C₁₋₆ alkyl and C₃₋₆ cycloalkyl, such ascyclopropyl; which alkyl groups are optionally substituted by one ormore substituents selected from E¹, e.g. fluoro), halo, —CN,—N(R^(f4))R^(f5) and —OR^(f7);

when R¹ represents —N(R^(N))R^(f5), then R^(f4) and R^(f5) preferablyand independently represent hydrogen or C₁₋₆ alkyl (optionallysubstituted by one or more halo atoms);

when R¹ represents —OR^(f7), then R^(f7) preferably represents C₁₋₆alkyl (optionally substituted by one or more halo atoms);

more preferably R¹ represents a substituent selected from hydrogen,—OCH(CH₃)₂ or, particularly, —OH, or, preferably, halo, —CN, —OCH₃,—OCH₂CH₃, —N(R^(f4))R^(f5) (e.g. —NH₂), —CH₃, —CH₂CH₃ and —CF₃.

Other preferred compounds of the invention that may be mentioned includethose in which ring A and ring B represent a fused bicyclic group of thefollowing structure:

Other preferred compounds of the invention that may be mentioned includethose in which ring A and ring B represent a fused bicyclic group of thefollowing structure:

In some embodiments, these fused bicyclic groups are unsubstituted. Inother embodiments they are substituted as described above in connectionwith rings A and B. In particular embodiments, the above-listed fused,bicyclic groups are optionally substituted by one or more substituentsselected from halo, C₁₋₃ alkyl, or —CN.

Particularly, for compounds in which ring A and ring B togetherrepresent a fused bicyclic group of formula IC, formula IC represents:

Hence preferred ring A/ring B bicyclic structures include those inwhich:

in formula IA: W^(1a) is CF, preferably, CH or N; W^(2a) is CF or,preferably, CH; W^(3a) is CR^(4a); W^(4a) is CR^(5a) or N; W^(5a) isCR^(6a);

R^(4a) and R^(6a) (particularly, R^(4a), R^(5a) and R^(6a))independently represent hydrogen;

one of W^(1a), W^(2a) and W^(3a) (preferably W^(1a)) may represent N orCH and the others represent CH;

one of W^(4a) and W^(5a) (preferably W^(4a)) represents N or CH and theother represents CH;

in formula IB: W^(1b) is CF or, preferably, CH or N; W^(2b) is CF or,preferably, CH; W^(3b) is CR^(4b) or N; W^(4b) is C or N; W^(5b) isCR^(6b); W^(6b) is C or N; W^(7b) is C;

R^(6b) (particularly, R^(4b) and R^(6b) independently) representshydrogen;

one of W^(4b) and W^(6b) represents C or N and the other represents C;

one of W^(1b), W^(2b) and W^(3b) (preferably W^(1b) or W^(3b)) mayrepresent N or CH and the others represent CH;

in formula IC: W^(1c) is O or, particularly, CR^(t1), preferably, CH orS; W^(2c) is CR^(t2), preferably, CH or S; W^(3c) is C; W^(4c) is N orCR^(5c) (preferably N); W^(5c) is CR^(6c); W^(6c) is C;

R^(6c) represents a C₁₋₃ alkyl group or, particularly, hydrogen;

one of W^(1c) and W^(2c) represents CH and the other represents O or,particularly, S;

one of W^(3c) and W^(6c) may represent N but preferably both representC;

one of W^(4c) and W^(5c) (preferably W^(4c)) may represent N (or CR^(5c)or CR^(6c)) and the other (preferably W^(5c)) represents CR^(5c) orCR^(6c);

in formula ID: W^(1d) is N; W^(2d) is S; W^(3d) is N; W^(4d) is CR^(5d);W^(5d) is C; W^(6d) is C;

R^(5d) represents hydrogen;

one of W^(3d) and W^(5d) may represent N and the other represents C;

one of W^(1d) and W^(2d) (preferably W^(1d)) represents N and the otherrepresents S.

Other preferred compounds of the invention that may be mentioned includethose in which:

Y represents -arylene- (e.g. -phenylene-), -heteroarylene- (e.g.1,2,3,4-tetrahydroisoquinolinyl, thiophenyl (i.e. thienyl), furanyl or,particularly, pyridyl or pyrazolyl), -heterocycloalkylene- (e.g.piperidinyl or morpholinyl, optionally containing a double bond) or—C₁₋₆alkylene-, all of which groups are optionally substituted asdefined herein (e.g. by E³, E⁴ and, if appropriate by ═O);

more preferably Y represents a cyclic group, e.g. optionally substitutedarylene, heteroarylene or heterocycloalkylene;

more preferably still Y represents one of the following groups (inwhich, preferably, the upper squiggly line represents the point ofattachment to the Z group):

e.g. more preferably:

more preferably still Y represents one of the following groups (inwhich, preferably, the upper squiggly line represents the point ofattachment to the X group):

or particularly, Y represents one of the following groups (in which,preferably, the upper squiggly line represents the point of attachmentto the X group):

Other preferred compounds of the invention include those in which:

X represents —N(R^(c))— or, more preferably a direct bond;

X may represent a linker group (i.e. other than a direct bond)particularly in the case when Y represents a non-cyclic group (e.g.acyclic C₁₋₁₂alkylene, optionally substituted as defined herein);

R^(c) represents hydrogen;

Z represents -(A^(x))₁₋₆- (e.g. -(A^(x))₂₋₆-);

each A^(x) independently represents —C(R^(x1))(R^(x2))—, —N(R^(x3))— and—C(O)—.

Further preferred compounds of the invention that may be mentionedinclude those in which:

R^(x1) and R^(x2) independently represent hydrogen, halo or C₁₋₆ (e.g.C₁₋₃) alkyl (preferably unsubstituted);

R^(x3) represents hydrogen or C₁₋₆ (e.g. C₁₋₃) alkyl (preferablyunsubstituted);

more preferably, R^(x1), R^(x2) and R^(x3) each independently representC₁₋₃ alkyl or, particularly, hydrogen;

each E_(x) independently represents halo, —C(O)R^(y1), C₁₋₆ alkyl orheterocycloalkyl (which latter two groups may be attached to a singlecarbon atom, and both of which are optionally substituted by one or morehalo, e.g. fluoro, atoms) (more preferably each E_(x) represents halo orunsubstituted C₁₋₆ alkyl); and/or

each R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(y1), R^(y2),R^(y3) and R^(y4) independently represent hydrogen or C₁₋₂ alkyloptionally substituted by one or more fluoro atoms.

Most preferred compounds of the invention include those in which:

E¹, E², E³, E⁴ and E⁵ independently represent, on each occasion whenused herein, Q⁴ or C₁₋₆ (e.g. C₁₋₃) alkyl optionally substituted by oneor more substituents selected from ═O and, preferably, Q⁵ (mostpreferably such E¹ to E⁵ groups represent Q⁴);

each Q⁴ and Q⁵ independently represents, on each occasion when usedherein halo, —CN, —N(R²⁰)R²¹, —OR²⁰, —C(═Y¹)—R²⁰, —C(═Y¹)—OR²⁰,—C(═Y¹)N(R²⁰)R²¹, —N(R²²)C(═Y¹)R²¹, —N(R²²)C(═Y¹)OR²¹, —NR²²S(O)₂R²⁰,—S(O)₂N(R²⁰)R²¹, —S(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, or C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from fluoro;

each Y¹ independently represents, on each occasion when used herein, ═O;

each R²⁰, R²¹, R²² and R²³ independently represent, on each occasionwhen used herein, hydrogen or C₁₋₃ alkyl optionally substituted by oneor more substituents selected from J⁴ and ═O; or

any pair of R²⁰, R²¹ and R²² (e.g. R²⁰ and R²¹)) may be linked togetherto form (e.g. when attached to the same nitrogen atom, along with therequisite nitrogen atom to which they are attached) a 4- to 8-memberedring, optionally containing one or more double bonds (e.g. one or two),and which ring may contain a further two or, preferably, one heteroatom(preferably selected from nitrogen and, especially, oxygen), and whichring is optionally substituted by one or more substituents selected fromJ⁶ and ═O;

each J¹, J², J⁴ and J⁶ independently represents, on each occasion whenused herein: (i) Q⁷; or (ii) C₁₋₈ (e.g. C₁₋₃) alkyl optionallysubstituted by one or more substituents selected from ═O and Q⁸ (morepreferably, each J¹, J², J⁴ and J⁶ (e.g. each J¹ and J²) independentlyrepresents Q⁷);

each Q⁷ and Q⁸ (e.g. Q⁷) independently represents —N(R⁵⁰)R⁵¹, —OR⁵⁰ or,preferably, halo (e.g. fluoro) or C₁₋₃ alkyl (e.g. methyl) optionallysubstituted by one or more fluoro atoms;

each Y^(a) independently represents ═O;

each R⁵⁰, R⁵¹, R⁵² and R⁵³ substituent independently represents, on eachoccasion when used herein, hydrogen or C₁₋₆ (e.g. C₁₋₃) alkyl optionallysubstituted by one or more substituents selected from fluoro;

R⁶⁰, R⁶¹ and R⁶² independently represent methyl or hydrogen.

Preferred aryl/arylene and heteroaryl/heteroarylene groups that Y mayindependently represent include optionally substituted1,2,3,4-tetrahydroisoquinolinyl or, particularly, optionally substitutedphenyl, naphthyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, pyrazolyl, pyridyl, indazolyl, indolyl,indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinolizinyl,benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl,pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl,quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl,benzothiazolyl, and/or benzodioxanyl.

Preferred compounds of the invention include those in which:

each E¹, E², E³, E⁴ and E⁵ independently represent C₁₋₆ (e.g. C₁₋₃)alkyl, heterocycloalkyl (which latter two groups are optionallysubstituted by one or more substituents selected from ═O and,preferably, Q⁵) or E¹ to E⁵ independently (and more preferably)represent Q⁴ (in which E⁴ is preferably halo (e.g. fluoro));

each Q⁴ and Q⁵ (e.g. Q⁴) independently represent halo (e.g fluoro),—C(═Y¹)—OR²⁰, —N(R²⁰)R²¹, —C(═Y¹)N(R²⁰)R²¹ or —N(R²²)C(═Y¹)OR²¹(preferably, halo (e.g fluoro), —C(═Y¹)—OR²⁰, —N(R²⁰)R²¹ or—C(═Y¹)N(R²⁰)R²¹);

each Y¹ independently represents ═S or, preferably, ═O;

R²⁰, R²¹ and R²² (e.g. R²⁰ and R²¹) independently represent hydrogen or,preferably, C₁₋₄ alkyl; or

R²⁰ and R²¹, when attached to the same nitrogen atom are linked togetherto form a 5- or 6-membered ring, optionally containing a furtherheteroatom (e.g. nitrogen, or, preferably, oxygen) so forming, e.g. amorpholinyl group;

R²² represents hydrogen.

More preferred compounds of the invention include those in which:

each R¹, R^(2a), R^(2b), R^(2c), R³, R^(4a), R^(5a), R^(6a), R^(4b),R^(6b), R^(5c), R^(6c) and R^(5d) are independently selected from:

(i) hydrogen;

(ii) halo, —CN, —OR^(f7) and/or —N(R^(f4))R^(f5); and/or

(iii) C₁₋₆ alkyl optionally substituted by one or more substituentsselected from ═O and E¹;

X represents a direct bond, —O—, —S— or —N(R^(c))—;

each R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) independentlyrepresent hydrogen or C₁₋₄ alkyl optionally substituted by one or morehalo atoms.

Most preferred compounds of the invention that may be mentioned includethose in which:

ring A/B represents formula IA, formula IB or formula ID, optionallysubstituted as indicated above, especially one of the following formulae(optionally substituted as indicated above):

R¹ represents a substituent selected from —OR^(f7) (in which R^(f7)preferably represents hydrogen or, especially, C₁₋₄ alkyl, which ispreferably unsubstituted, e.g. R^(f7) is most preferably unsubstitutedC₁₋₃ alkyl (particularly unsubstituted C₁₋₂ alkyl (e.g. methyl));

R^(2a) and R^(2c) independently represent hydrogen, C₁₋₃ alkyloptionally substituted by halo (e.g. fluoro), or a substituent selectedfrom halo (e.g. fluoro);

R^(2b) and R³ independently represent hydrogen;

X represents a direct bond or —N(R^(c))—;

R^(c) represents hydrogen;

Y preferably represents pyrazolyl (e.g. 1,4-linked; i.e. linked at the4-position to the requisite bicycle of formula I),1,2,3,4-tetrahydroisoquinolinyl (e.g. 2,7-linked;

i.e. linked at the 7-position to the requisite bicycle of formula I),thiophenyl (e.g. 2,5-linked), furanyl (e.g. 2,5-linked),dihydropiperidinyl (e.g. 1,4-linked; i.e. linked at the 4-position tothe requisite bicycle of formula I), morpholinyl (e.g. 2,4-linked; i.e.linked at the 4-position to the requisite bicycle of formula I) or,particularly, pyridyl (e.g. 3,5-linked or 2,4-linked; in the lattercase, linked to the requisite bicycle of formula I at the 4-position ofthe pyridyl), phenyl (1,3-linked), piperidinyl (1,4-linked; i.e. linkedat the 1-position to the requisite bicycle of formula I) orunsubstituted acyclic C₁₋₄ alkylene;

when Y represents arylene or heteroarylene, such groups are optionallysubstituted by one or more (e.g. two or preferably one) substituent(s)selected from E³ (which E³ substituent may be located at either of thepositions ortho to the point of attachment to the requisite bicycle offormula I);

when Y represents pyridyl (or pyridylene), then that moiety is linked toZ and X via non-adjacent atoms that are in a 1,3-relative relationship;

when Y represents heterocycloalkylene or alkylene, such groups arepreferably unsubstituted;

when Y represents alkylene, then X may represent —N(R^(c))— (e.g. —Y—X—may represent —C₁₋₄alkylene-N(R^(c))—);

when Y represents -arylene-, -heteroarylene- or -heterocycloalkylene-,then X preferably represents a direct bond;

E³ represents Q⁴;

Q⁴ represents halo (e.g. fluoro);

Z represents —C(O)-[T¹]- or —C(O)N(R^(x3))-[T¹]-, in which T¹ represents—(CH₂)₀₋₄-T²- (e.g. —(CH₂)₄-T²-, —CH₂-T²- or, particularly, -T²-) and T²represents a direct bond or —C(O)—N(H)—CH₂—; or, particularly, Zrepresents —C(O)N(H)-[T¹], in which T¹ represents —(CH₂)₁₋₄-T²- (e.g.—(CH₂)₄-T²- or preferably —CH₂-T²-) and T² represents a direct bond or—C(O)—N(H)—CH₂—.

In certain embodiments of the invention, ring A and ring B represent afused bicyclic group of any one of the following formulae:

wherein

in formula IA: W^(1a) is CH, CF or N; W^(4a) is CR^(5a) or N;

in formula IB: W^(1b) is CH, CF or N; W^(3b) is CR^(4b) or N; W^(4b) isC or N; W^(6b) is C or N;

and wherein when W^(3b) represents N and W^(4b) and W^(6b) represent C,then R* is hydrogen (in all other cases R* is absent);

in formula IC: W^(1c) is CH, CR^(t1), N, NR^(q1), O or S; W^(2c) is CH,CR^(t2), N, NR^(q2), O or S;

W^(4c) is CR^(5c) or N; W^(5c) is CR^(6c) or N;

in formula ID: W^(1d) is CH, CR^(t3), N, NR^(q3), O or S; W^(2d) is CH,CR^(t4), N, NR^(q4), O or S; W^(3d) is C or N; W^(6d) is C or N;

each R^(t1), R^(t2), R^(t3) and R^(t4) is independently selected fromhalo, C₁₋₃ alkyl (e.g. acyclic C₁₋₃ alkyl or cyclopropyl), —OR^(s1), or—CN;

R^(s1) represents hydrogen or C₁₋₂ alkyl;

each R^(q1), R^(q2), R^(q3) and R^(q4) is independently selected fromC₁₋₃ alkyl (e.g. acyclic C₁₋₃ alkyl or cyclopropyl), or —C(O)CH₃;

each R¹, R^(2a), R^(2b), R^(2c), R³, R^(5a), R^(6a), R^(4b), R^(5a),R^(5c) and R^(6c) are independently selected from hydrogen or asubstituent selected from halo, —C(O)R^(f3), —N(R^(f4))R^(f5), —OR^(f7)or C₁₋₈ alkyl (e.g. acyclic C₁₋₆ alkyl or C₃₋₇ cycloalkyl) which alkylgroup is optionally substituted by one or more substituents selectedfrom ═O and E¹;

R^(f4), R^(f5) and R^(f7) independently represent hydrogen or C₁₋₆ alkyloptionally substituted by one or more substituents selected from ═O andE²;

R^(f3) represents C₁₋₆ alkyl optionally substituted by one or moresubstituents selected from ═O and E²;

X represents a direct bond, —C(R^(a))(R^(b))—, —O—, —S—, —N(R^(c))—;

Y represents -arylene-, -heteroarylene- (which latter two groups areoptionally substituted by one or more substituents selected from E³),-heterocycloalkylene- or —C₁₋₆alkylene- (which latter two groups areoptionally substituted by one or more substituents selected from ═O andE⁴);

R^(N) represents hydrogen or C₁₋₃ alkyl optionally substituted by one ormore substituents selected from ═O and E⁵;

Z represents -(A^(x))₁₋₆- wherein each A^(x) independently represents—C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—, —O—;

R^(x1), R^(x2) and R^(x3) each independently represents hydrogen, halo,—C(O)R^(y1) or C₁₋₆ alkyl (which latter group is optionally substitutedby one or more halo atoms);

R^(y1) represents hydrogen or C₁₋₃ alkyl;

each R^(a), R^(b) and R^(c) independently represent hydrogen or C₁₋₃alkyl optionally substituted by one or more halo atoms; and/or

each E¹, E², E³, E⁴ and E⁵ independently represents, on each occasionwhen used herein, halo or C₁₋₄ alkyl or heterocycloalkyl, both of whichare optionally substituted by one or more halo atoms.

In certain embodiments of the invention, ring A and ring B represent afused bicyclic group of any one of the following formulae:

wherein

in formula IA: W^(1a) is CH, CF or N; W^(4a) is CR^(5a) or N;

in formula IB: W^(1b) is CH, CF or N; W^(3b) is CR^(4b) or N; W^(4b) isC or N; W^(6b) is C or N;

and wherein when W^(3b) represents N and W^(4b) and W^(6b) represent C,then R* is hydrogen (in all other cases R* is absent);

in formula IC: W^(1c) is CH, CR^(t1), N, NR^(q1), O or S; W^(2c) is CH,CR^(t2), N, NR^(q2), O or S; W^(4c) is CR^(5c) or N; W^(5c) is CR^(6c)or N;

in formula ID: W^(1d) is CH, CR^(t3), N, NR^(q3), O or S; W^(2d) is CH,CR^(t4), N, NR^(q4), O or S; W^(3d) is C or N; W^(6d) is C or N;

each R^(t1), R^(t2), R^(t3) and R^(t4) is independently selected fromhalo, C₁₋₃ alkyl (e.g. acyclic C₁₋₃ alkyl or cyclopropyl), —OR^(s1), or—CN;

R^(s1) represents hydrogen or C₁₋₂ alkyl;

each R^(q1), R^(q2), R^(q3) and R^(q4) is independently selected fromC₁₋₃ alkyl (e.g. acyclic C₁₋₃ alkyl or cyclopropyl), or —C(O)CH₃;

each R¹, R^(2a), R^(2b), R^(2c), R³, R^(5a), R^(6a), R^(4b), R^(5a),R^(5c) and R^(6c) are independently selected from hydrogen or asubstituent selected from halo, —C(O)R^(f3), —N(R^(f4))R^(f5), —OR^(f7)or C₁₋₈ alkyl (e.g. acyclic C₁₋₆ alkyl or C₃₋₇ cycloalkyl) which alkylgroup is optionally substituted by one or more substituents selectedfrom ═O and E¹;

R^(f4), R^(f5) and R^(f7) independently represent hydrogen or C₁₋₆ alkyloptionally substituted by one or more substituents selected from ═O andE²;

R^(f3) represents C₁₋₆ alkyl optionally substituted by one or moresubstituents selected from ═O and E²;

X represents a direct bond, —C(R^(a))(R^(b))—, —O—, —S—, —N(R^(c))—;

Y represents -arylene-, -heteroarylene- (which latter two groups areoptionally substituted by one or more substituents selected from E³),-heterocycloalkylene- or —C₁₋₆alkylene- (which latter two groups areoptionally substituted by one or more substituents selected from ═O andE⁴);

R^(N) represents hydrogen or C₁₋₃ alkyl optionally substituted by one ormore substituents selected from ═O and E⁵;

Z represents -(A^(x))₁₋₆- wherein each A^(x) independently represents—C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—, —O—;

R^(x1), R^(x2) and R^(x3) each independently represents hydrogen, halo,—C(O)R^(y1) or C₁₋₆ alkyl (which latter group is optionally substitutedby one or more halo atoms);

R^(y1) represents hydrogen or C₁₋₃ alkyl;

each R^(a), R^(b) and R^(c) independently represent hydrogen or C₁₋₃alkyl optionally substituted by one or more halo atoms; and/or

each E¹, E², E³, E⁴ and E⁵ independently represents, on each occasionwhen used herein, halo, C₁₋₄ alkyl, —O—C₁₋₄ alkyl or heterocycloalkyl,which latter three groups are optionally substituted by one or more haloatoms.

In a further embodiment of the invention, ring A and ring B represent afused bicyclic group of any one of the following formulae:

wherein

in formula IA: W^(1a) is CH or N; W^(4a) is CH or N;

in formula IB: W^(1b) is CH or N; W^(3b) is CH or N; W^(4b) is C or N;W^(6b) is C or N; and

wherein when W^(3b) represents N and W^(4b) and W^(6b) represent C, thenR* is hydrogen (in all other cases R* is absent);

in formula IC: W^(1c) is CH or S; W^(2c) is CH, C(CH₃) or S; W^(4c) isCH, C(CN) or N; W^(5c) is CH, C(CH₃) or C—CH(CH₃)₂;

in formula ID: W^(1d) is N; W^(2d) is S; W^(3d) is N; W^(6d) is C;

each R¹, R^(2a), R^(2b), R^(2c), R³, are independently selected fromhydrogen or a substituent selected from halo, —OR^(f7) or C₁₋₄ alkyl;

R^(f7) independently represent hydrogen or C₁₋₄ alkyl optionallysubstituted by one or more substituents selected from E²;

X represents a direct bond;

Y represents -arylene-, -heteroarylene- (which latter two groups areoptionally substituted by one or more substituents selected from E³),-heterocycloalkylene- or —C₁₋₆alkylene- (which latter two groups areoptionally substituted by one or more substituents selected from E⁴);

R^(N) represents hydrogen;

Z represents -(A^(x))₁₋₄- wherein each A^(x) independently represents—C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—;

R^(x1), R^(x2) and R^(x3) each independently represents hydrogen, halo,C₁₋₆ alkyl (which latter group is optionally substituted by one or morehalo atoms);

each E², E³ and E⁴ independently represents, on each occasion when usedherein, halo, C₁₋₄ alkyl, —O—C₁₋₄ alkyl or heterocycloalkyl, whichlatter three groups are optionally substituted by one or more haloatoms.

In a further embodiment of the invention, ring A and ring B represent afused bicyclic group of any one of the following formulae:

wherein

in formula IA: W^(1a) is CH or N; W^(4a) is CH or N;

in formula IB: W^(1b) is CH or N; W^(3b) is CH; W^(4b) is C or N; W^(6b)is C or N; and wherein R* is absent;

in formula IC: W^(1c) is S; W^(2c) is CH or C(CH₃); W^(4c) is N; W^(6b)is CH or C(CH₃);

each R¹, R^(2a), R^(2b), R^(2c), R³, are independently selected fromhydrogen or a substituent selected from halo, —OR^(f7) or C₁₋₄ alkyl;

R^(f7) independently represent hydrogen or C₁₋₄ alkyl optionallysubstituted by one or more substituents selected from E²;

X represents a direct bond;

Y represents -phenyl-, -pyridinyl-, -piperidinyl-, -pyrazolyl-,tetrahydroisoquinolinyl- or -thiophenyl- (which groups are optionallysubstituted by one or more substituents selected from E³),-tetrahydropyridinyl-, -morpholinyl- or -pyrrolidinyl- (which latterthree groups are optionally substituted by one or more substituentsselected from E⁴);

R^(N) represents hydrogen;

Z represents -(A^(x))₁₋₄- wherein each A^(x) independently represents—C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—;

R^(x1), R^(x2) and R^(x3) each independently represents hydrogen, halo,C₁₋₆ alkyl (which latter group is optionally substituted by one or morehalo atoms);

each E², E³ and E⁴ independently represents, on each occasion when usedherein, halo, C₁₋₄ alkyl, —O—C₁₋₄ alkyl or heterocycloalkyl, whichlatter three groups are optionally substituted by one or more haloatoms.

In a further embodiment of the invention, ring A and ring B represent afused bicyclic group of any one of the following formulae:

wherein

in formula IC: W^(1c) is S; W^(2c) is CH or C(CH₃); W^(4c) is CH, C(CN)or N; W^(5c) is CH;

each R¹, R^(2a), R^(2b), R^(2c), R³, are independently selected fromhydrogen or a substituent selected from halo, or —OR^(f7);

R^(f7) independently represent hydrogen or C₁₋₃ alkyl optionallysubstituted by one or more substituents selected from E²;

X represents a direct bond;

Y represents -pyridyl-, -thiophenyl- (which two groups are optionallysubstituted by one or more substituents selected from E³), -morpholinyl-or -pyrrolidinyl- (which latter two groups are optionally substituted byone or more substituents selected from E⁴);

R^(N) represents hydrogen;

Z represents -(A^(x))₁₋₃- wherein each A^(x) independently represents—C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—;

R^(x1), R^(x2) and R^(x3) each independently represents hydrogen, orC₁₋₃ alkyl;

each E², E³ and E⁴ independently represents, on each occasion when usedherein, halo, C₁₋₄ alkyl or heterocycloalkyl, which latter three groupsare optionally substituted by one or more halo atoms.

In particular embodiments, the compounds of the invention may be in anisolated form, and/or ex vivo.

Particularly preferred compounds of the invention include those of theexamples described hereinafter.

Compounds of the invention may be made in accordance with techniquesthat are well known to those skilled in the art, for example asdescribed hereinafter.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I which processcomprises:

(i) compounds of formula I in which Z contains a —C(O)N(R^(x3))— or—N(R^(x3))C(O)— moiety, may be prepared by intramolecular reaction of acompound of formula II,

wherein Z¹ and Z² independently represent —C(O)OH, —N(R^(x3))H or apartial Z moiety with a terminal —C(O)OH group or terminal —N(R^(x3))Hgroup (or derivatives thereof, such as carboxylic acid esterderivatives) and wherein one of Z¹ and Z² contains the —C(O)OH group (orderivative) and the other contains the —N(R^(x3))H group (orderivative), and ring A/ring B, R¹, R^(2a), R^(2b), R^(2c), R³, X and Yare as hereinbefore defined, which reaction is an amide coupling, whichmay be performed under standard reaction conditions, for instance thereaction may be performed in the presence of a suitable coupling reagent(e.g. 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or hydrochloridethereof), N,N′-disuccinimidyl carbonate,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,2-(1H-benzotriazol-1-yl)-1, 1,3, 3-tetramethyluroniumhexa-fluorophosphate, benzotriazol-1-yloxytris-pyrrolidinophosphoniumhexafluoro-phosphate, bromo-tris-pyrrolidinophosponiumhexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetra-fluorocarbonate, 1-cyclohexyl-carbodiimide-3-propyloxymethylpolystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, O-benzotriazol-1-yl-N, N,N′,N′-tetramethyluroniumtetrafluoroborate and/or 1-hydroxy-7-azabenzotriazole), optionally inthe presence of a suitable base (e.g. sodium hydride, sodiumbicarbonate, potassium carbonate, pyridine, triethylamine,dimethylaminopyridine, diisopropylamine, diisopropylethylamine, sodiumhydroxide, potassium tert-butoxide, dimethylaminopyridine and/or lithiumdiisopropylamide (or variants thereof), an appropriate solvent (e.g.tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform,acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane ortriethylamine) and a further additive (e.g. 1-hydroxybenzotriazolehydrate). Preferred amide coupling reaction conditions include reactionin the presence of a coupling reagent HATU, PyBOP and/or HOAt, in thepresence of a base (preferably DIPEA and, optionally DMAP) and solvent(preferably DMF). In the case when reaction is performed on an esterfunctional group (e.g. —C(O)OCH₃ or —C(O)OCH₂CH₃), in the presence ofe.g. trimethylaluminium, or, alternatively the —C(O)OH group may firstbe activated to the corresponding acyl halide (e.g—C(O)Cl, by treatmentwith oxalyl chloride, thionyl chloride, phosphorous pentachloride,phosphorous oxychloride, or the like), under standard conditions knownto those skilled in the art (e.g. optionally in the presence of asuitable solvent, suitable base and/or in an inert atmosphere);

(ii) compounds of formula I in which Z contains —O—, —S— or —N(R^(x3))—,may be prepared by reaction of a compound of formula III,

wherein Z³ represents —OH, —SH, —N(R^(x3))H or -L^(x) (in which L^(x) isa suitable leaving group, such as chloro, bromo, iodo or a sulfonategroup such as —OS(O)₂CF₃, —OS(O)₂CH₃ or —OS(O)₂PhMe), or Z³ contains apartial Z moiety with a terminal —OH, —N(R^(x3))H or -L^(x) group and Z⁴represents L^(y)-, HO—, HS— or H(R^(x3))N— (as appropriate) or a partialZ moiety with a terminal L^(y)-, HO— or H(R^(x3))N—, L^(y) is a suitableleaving group (such as one defined for L^(x)) and ring A/ring B, R¹,R^(2a), R^(2b), R^(2c), R³, X and Y are as hereinbefore defined (inwhich one of Z³ and Z⁴ contains a —OH, —SH or —N(R^(x3))H moiety and theother contains the L^(x) or L^(y) moiety), which reaction may beperformed under standard nucleophilic substitution reaction conditions,for instance in the presence of a suitable base (e.g. sodium hydride,sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine,triethylamine, tributylamine, trimethylamine, dimethylaminopyridine,diisopropylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide,N-ethyldiisopropylamine, N-(methylpolystyrene)-4-(methylamino)pyridine,potassium bis(trimethylsilyl)-amide, sodium bis(trimethylsilyl)amide,potassium tert-butoxide, lithium diisopropylamide, lithium2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriatesolvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane,chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene,dioxane or triethylamine). However, if there is a L^(x) or L^(y) groupdirectly attached to an aromatic ring, and reaction is performed with anucleophilic —OH or —N(R^(x3))H (or the like) moiety, the reaction maybe performed in the presence of an appropriate metal catalyst (or a saltor complex thereof) such as Cu, Cu(OAc)₂, CuI (or CuI/diamine complex),copper tris(triphenyl-phosphine)bromide, Pd(OAc)₂,tris(dibenzylideneacetone)-dipalladium(0) (Pd₂(dba)₃) or NiCl₂ and anoptional additive such as Ph₃P,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or anappropriate crown ether such as 18-crown-6-benzene, in the presence ofan appropriate base such as NaH, Et₃N, pyridine,N,N′-dimethylethylenediamine, Na₂CO₃, K₂CO₃, K₃PO₄, Cs₂CO₃, t-BuONa ort-BuOK (or a mixture thereof, optionally in the presence of 4 Åmolecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane,toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol,ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile,dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixturethereof). This reaction may be carried out under microwave irradiationreaction conditions or, alternatively, the reaction may be performed inthe absence of other reagents such as catalyst, base and even solvent;

(iii) compounds of formula I in which R^(x3), R^(y2), R^(y3) and/orR^(y4) represent optionally substituted C₁₋₆ or C₁₋₃ alkyl, may beprepared by reaction of a corresponding compound of formula I in whichR^(x3), R^(y2), R^(y3) and/or R^(y4) represent hydrogen, with a compoundof formula IV,L¹-R¹²⁻¹⁴  IV

wherein R¹²⁻¹⁴ represents R^(x3), R^(y2), R^(y3) or R^(y4) (asappropriate/required) and L¹ represents a suitable leaving group asdefined for L^(x) (e.g. under standard alkylation reaction conditions,such as reaction in the presence of base and solvent, e.g. underconditions such as those mentioned in step (ii) above), or with acompound of formula V,H(O)C—R^(12a-14a)  V

wherein R^(12a-14a) represents C₁₋₅ or C₁₋₂ alkyl optionally substitutedby one or more halo atoms, under reductive amination reaction conditions(for example in the presence of a chemoselective reducing agent such assodium triacetoxyborohydride or sodium cyanoborohydride, oralternatively, as a two-step process including condensation and thenreduction, which reduction step in this instance may be performed in thepresence of a stronger reducing agent such as sodium borohydride orLiAlH₄);

(iv) compounds of formula I containing a —N(R)—CH₂— moiety (e.g. when Zcontains a —N(R^(x3))—CH₂— moiety) may be prepared by reduction of acorresponding compound of formula I containing a —N(R)C(O)— moiety (e.g.when Z contains a —N(R^(x3))—C(O)— moiety), for example in the presenceof appropriate reduction reaction conditions, e.g. in the presence of achemoselective reducing agent such as LiAlH₄.

Compounds of formula II and III may be prepared by reaction of acompound of formula VI,

wherein L² represents a suitable leaving group, such as such as iodo,bromo, chloro, a sulfonate group (e.g. —OS(O)₂CF₃, —OS(O)₂CH₃ or—OS(O)₂PhMe), or a sulfide group (e.g. —S—C₁₋₆ alkyl, such as —SCH₃),Z¹⁻³ represents Z¹ or Z³ (depending on whether compound of formula II orIII is being prepared) and R¹, R^(2a), R^(2b), R^(2c), R³ and ring A/Bare as hereinbefore defined, with a compound of formula VII,L³-X—Y—Z²⁻⁴  VII

wherein Z²⁻⁴ represents Z² or Z⁴, L³ represents a suitable group, suchas:

-   -   (a) —B(OH)₂, —B(OR^(wx))₂ or —Sn(R^(wx))₃, in which each R^(wx)        independently represents a C₁₋₆ alkyl group, or, in the case of        —B(OR^(wx))₂, the respective R^(wx) groups may be linked        together to form a 4- to 6-membered cyclic group (such as a        4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), thereby        forming e.g. a pinacolato boronate ester group, (or L³ may        represent iodo, bromo or chloro, provided that L² and L³ are        mutually compatible), for instance when X represents a direct        bond or —C(R^(a))(R^(b))—; or    -   (b) hydrogen, for instance when X represents —O—, —S— or        —N(R^(c))—,

and X and Y are as hereinbefore defined, under standard reactionconditions, for instance for (b) above, under reaction conditions suchas those hereinbefore described in respect of process (ii) above (e.g.catalytic reaction conditions) or for (a) above may be performed forexample in the presence of a suitable catalyst system, e.g. a metal (ora salt or complex thereof) such as Pd, CuI, Pd/C, PdCl₂, Pd(OAc)₂,Pd(Ph₃P)₂Cl₂, Pd(Ph₃P)₄ (i.e. palladium tetrakistriphenylphosphine),Pd₂(dba)₃ and/or NiCl₂ (preferred catalysts include palladium) and aligand such as PdCl₂(dppf).DCM, t-Bu₃P, (C₆H₁₁)₃P, Ph₃P, AsPh₃,P(o-Tol)₃, 1,2-bis(diphenylphosphino)ethane,2,2′-bis(di-tert-butylphosphino)-1,1′-biphenyl,2,2′-bis(diphenylphosphino)-1,1′-bi-naphthyl,1,1′-bis(diphenyl-phosphino-ferrocene),1,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof(preferred ligands include PdCl₂(dppf).DCM), together with a suitablebase such as, Na₂CO₃, K₃PO₄, Cs₂CO₃, NaOH, KOH, K₂CO₃, CsF, Et₃N,(i-Pr)₂NEt, t-BuONa or t-BuOK (or mixtures thereof; preferred basesinclude Na₂CO₃ and K₂CO₃) in a suitable solvent such as dioxane,toluene, ethanol, dimethylformamide, dimethoxyethane, ethylene glycoldimethyl ether, water, dimethylsulfoxide, acetonitrile,dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or mixturesthereof. When L³ represents a sulfide (e.g. —SCH₃), then an additivesuch as CuMeSaI (copper(I) 3-methylsalicylate) or CuTC(copper(I)thiophene-2-carboxylate) may also be employed. The reactionmay be carried out for example at room temperature or above (e.g. at ahigh temperature such as at about the reflux temperature of the solventsystem). Alternative reaction conditions include microwave irradiationconditions, for example at elevated temperature, e.g. of about 130° C.

Alternatively, compounds of formula II or III may be prepared byreaction of a compound of formula VIII,

wherein R¹, X, Y, Z²⁻⁴ and ring A/B are as hereinbefore defined, with acompound of formula IX,

wherein L⁴ represents —OH or chloro, bromo or iodo (preferably, chloro),and Z¹⁻³, R^(2a), R^(2b), R^(2c) and R³ are as hereinbefore defined, forexample under reaction conditions such as those hereinbefore describedin respect of process step (i) above (sulfonamide coupling reactionconditions).

Compounds of formula II or Ill in which X represents —C(O)N(R^(e))— or—N(R^(f))—C(O)—N(R^(g))— may be prepared by reaction of a correspondingcompound of formula X,

wherein Z¹⁻³, R¹, R^(2a), R^(2b), R^(2c), R³ and ring A/B are ashereinbefore defined, with a compound of formula XI,L⁴-X^(a)—Y—Z²⁻⁴  XI

wherein X^(a) represents —C(O)— or —C(O)—N(R^(f))— and L⁴ represents asuitable leaving group (such as one hereinbefore defined in respect ofL^(x)) and Y and Z²⁻⁴ are as hereinbefore defined, under standardreaction conditions, such as those hereinbefore described in respect ofprocess step (i);

Compounds of formula II or III in which X represents —N(R^(d))C(O)— maybe prepared by reaction of a corresponding compound of formula XII,

wherein L⁵ represents —OH or a suitable leaving groups (such as onehereinbefore defined for L^(x), e.g. chloro) and Z¹⁻³, R¹, R^(2a),R^(2b), R^(2c), R³ and ring A/B are as hereinbefore defined, with acompound of formula XIII,HN(R^(d))—Y—Z²⁻⁴  XIII

wherein R^(d), Y and Z²⁻⁴ are as hereinbefore defined, under standardreaction conditions, such as those hereinbefore described in respect ofprocess step (i).

Compounds of formula VI may be prepared by reaction of a compound offormula XIV,

wherein L², R¹ and ring A/B are as hereinbefore defined, with a compoundof formula IX as hereinbefore defined, under reaction conditions such asthose hereinbefore described in respect of process step (i) above(sulfonamide coupling reaction conditions).

Compounds of formula VI and XIV in which L² represents halo, may beprepared by reaction of a compound corresponding to a compound offormula VI and XIV but in which L² represents hydrogen, with a source ofhalide ions, for instance an electrophile that provides a source ofiodide ions includes iodine, diiodoethane, diiodotetrachloroethane or,preferably, N-iodosuccinimide, a source of bromide ions includesN-bromosuccinimide and bromine, and a source of chloride ions includesphosphorus oxychloride (POCl₃), N-chlorosuccinimide, chlorine and iodinemonochloride.

Other compounds of formula VI and XIV may also be prepared understandard conditions, for instance such as those described herein, forexample, for synthesis of those compounds in which L² represents asulfonate group, reaction of a corresponding compound but in which L²represents —OH with an appropriate sulfonyl halide, under standardreaction conditions, such as in the presence of a base (e.g. ashereinbefore described in respect of preparation of compounds of formulaI (process step (ii)).

Compounds of formula XII may be prepared by reaction of a compound offormula VI as hereinbefore defined, with an appropriate reagent for theintroduction of the —C(O)OH (or —C(O)Cl) group, for instance bymetallation of the L² group (e.g. conversion to the correspondinglithiated derivative) and then quench with e.g. CO₂ or phosgene,triphosgene or the like, under conditions known to those skilled in theart.

Compounds of formula XIV may be prepared by reaction of a compound offormula XV,

wherein L⁶ represents a suitable leaving group such as one hereinbeforedefined by L², and L², ring A/B are as hereinbefore defined, with acompound of formula XVI,

wherein L⁷ represents a suitable group, such as one hereinbefore definedby L³, and R¹ is as hereinbefore defined, under standard reactionconditions known to those skilled in the art, for example thosedescribed in respect of preparation of compounds of formula II or III(reaction of a compound of formula VI and VII; see step (a)).

The core bicyclic ring structures A/B (e.g. of formulae VI, X and XIV)may be commercially available or prepared in accordance with knownstandard procedures (e.g. starting from known commercially availablestarting materials), for instance they may be prepared in accordancewith the procedures described in e.g. WO2009/040552, WO2008/150827 andWO 2010/112874.

Certain other intermediate compounds may also be commercially available,known in the literature, or may be obtained either by analogy with theprocesses described herein, or by conventional synthetic procedures, inaccordance with standard techniques, from available starting materialsusing appropriate reagents and reaction conditions. Further, the skilledperson will appreciate that where reactions to introduce the 3-pyridylmoiety of compounds of formula I is described, similar reactions may beperformed to introduce the “—X—Y—Z” moiety in compounds of formula I andvice versa. Further, processes to prepare compounds of formula I may bedescribed in the literature, for example in:

-   Werber, G. et al.; J. Heterocycl. Chem.; EN; 14; 1977; 823-827;-   Andanappa K. Gadad et al. Bioorg. Med. Chem. 2004, 12, 5651-5659;-   Paul Heinz et al. Monatshefte für Chemie, 1977, 108, 665-680;-   M. A. El-Sherbeny et al. Boll. Chim. Farm. 1997, 136, 253-256;-   Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.    2005, 44, 2-49;-   Bretonnet et al. J. Med. Chem. 2007, 50, 1872;-   Asunción Marin et al. Farmaco 1992, 47 (1), 63-75;-   Severinsen, R. et al. Tetrahedron 2005, 61, 5565-5575;-   Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.    2005, 44, 2-49;-   M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;-   Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65(20), 6319-6337;-   Shintani, R.; Okamoto, K. Org. Lett. 2005, 7 (21), 4757-4759;-   Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.    2005, 44, 2-49;-   J. Kobe et at, Tetrahedron, 1968, 24, 239;-   P. F. Fabio, A. F. Lanzilotti and S. A. Lang, Journal of Labelled    Compounds and Pharmaceuticals, 1978, 15, 407;-   F. D. Bellamy and K. Ou, Tetrahedron Lett., 1985, 25, 839;-   M. Kuwahara et al., Chem. Pharm Bull., 1996, 44, 122;-   A. F. Abdel-Magid and C. A Maryanoff. Synthesis, 1990, 537;-   M. Schlosser et al. Organometallics in Synthesis. A Manual, (M.    Schlosser, Ed.),-   Wiley &Sons Ltd: Chichester, U K, 2002, and references cited    therein;-   L. Wengwei et al., Tetrahedron Lett., 2006, 47, 1941;-   M. Plotkin et al. Tetrahedron Lett., 2000, 41, 2269;-   Seyden-Penne, J. Reductions by the Alumino and Borohydrides, VCH,    NY, 1991;-   O. C. Dermer, Chem. Rev., 1934, 14, 385;-   N. Defacqz, et al., Tetrahedron Lett., 2003, 44, 9111;-   S. J. Gregson et al., J. Med. Chem., 2004, 47, 1161;-   A. M. Abdel Magib, et al., J. Org. Chem., 1996, 61, 3849;-   A. F. Abdel-Magid and C. A Maryanoff. Synthesis, 1990, 537;-   T. Ikemoto and M. Wakimasu, Heterocycles, 2001, 55, 99;-   E. Abignente et al, II Farmaco, 1990, 45, 1075;-   T. Ikemoto et al., Tetrahedron, 2000, 56, 7915;-   T. W. Greene and P. G. M. Wuts, Protective Groups in Organic    Synthesis, Wiley, N Y, 1999;-   S. Y. Han and Y.-A. Kim. Tetrahedron, 2004, 60, 2447;-   J. A. H. Lainton et al., J. Comb. Chem., 2003, 5, 400; or-   Wiggins, J. M. Synth. Commun., 1988, 18, 741.

Other specific transformation steps (including those that may beemployed in order to form compounds of formula I) that may be mentionedinclude:

-   (i) reductions, for example of a carboxylic acid (or ester) to    either an aldehyde or an alcohol, using appropriate reducing    conditions (e.g. —C(O)OH (or an ester thereof), may be converted to    a —C(O)H or —CH₂—OH group, using DIBAL and LiAlH₄, respectively (or    similar chemoselective reducing agents));-   (ii) reductions of an aldehyde (—C(O)H) group to an alcohol group    (—CH₂OH), using appropriate reduction conditions such as those    mentioned at point (i) above;-   (iii) oxidations, for example of a moiety containing an alcohol    group (e.g. —CH₂OH) to an aldehyde (e.g. —C(O)H) or of a —S— moiety    to a —S(O)— or —S(O)₂— moiety (or the reverse reduction reaction),    for example in the presence of a suitable oxidising agent, e.g. MnO₂    or mcpba or the like;-   (iv) reductive amination of an aldehyde and an amine, under    appropriate reaction conditions, for example in “one-pot” procedure    in the presence of an appropriate reducing agent, such as a    chemoselective reducing agent such as sodium cyanoborohydride or,    preferably, sodium triacetoxyborohydride, or the like.    Alternatively, such reactions may be performed in two steps, for    example a condensation step (in the presence of e.g. a dehydrating    agent such as trimethyl orthoformate or MgSO₄ or molecular sieves,    etc) followed by a reduction step (e.g. by reaction in the presence    of a reducing agent such as a chemoselective one mentioned above or    NaBH₄, AlH₄, or the like), for instance the conversion of —NH₂ to    —N(H)-isopropyl by condensation in the presence of acetone    (H₃C—C(O)—CH₃) followed by reduction in the presence of a reducing    agent such as sodium cyanaoborohydride (i.e. overall a reductive    amination);-   (v) formation of an amide or sulfonamide, for example by reaction of    a sulfonyl chloride with an amine or by an amide coupling reaction,    i.e. the formation of an amide from a carboxylic acid (or ester    thereof), for example —C(O)OH (or an ester thereof), may be    converted to —C(O)N(R²⁰)R²¹ group (in which R²⁰ and R²¹ are as    hereinbefore defined, and may be linked together, e.g. as defined    above), and which reaction may (e.g. for —COOH) be performed in the    presence of a suitable coupling reagent (e.g.    1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, or the    like) or, in the case of an ester (e.g. —C(O)OCH₃ or —C(O)OCH₂CH₃),    be performed in the presence of e.g. trimethylaluminium, or,    alternatively the —C(O)OH group may first be activated to the    corresponding acyl halide (e.g —C(O)Cl, by treatment with oxalyl    chloride, thionyl chloride, phosphorous pentachloride, phosphorous    oxychloride, or the like), and, in all cases, the relevant compound    is reacted with a compound of formula HN(R²⁰R²¹ (in which R²⁰ and    R²¹ are as hereinbefore defined), under standard conditions known to    those skilled in the art (e.g. optionally in the presence of a    suitable solvent, suitable base and/or in an inert atmosphere);-   (vi) conversion of a primary amide to a nitrile functional group,    for example under dehydration reaction conditions, e.g. in the    presence of POCl₃, or the like;-   (vii) nucleophilic substitution (e.g. aromatic nucleophilic    substitution) reactions, where any nucleophile replaces a leaving    group, e.g. an amine may replace a —S(O)CH₃ leaving group;-   (viii) transformation of a methoxy group to a hydroxy group, by    reaction in the presence of an appropriate reagent, such as boron    fluoride-dimethyl sulfide complex or BBr₃ (e.g. in the presence of a    suitable solvent such as dichloromethane);-   (ix) haolgenation, alkylation, acylation or sulfonylation reactions,    which may be performed in the presence of base and solvent (such as    those described hereinbefore);-   (x) specific deprotection steps, such as deprotection of an N-Boc    protecting group by reaction in the presence of an acid, or, a    hydroxy group protected as a silyl ether (e.g. a    tert-butyl-dimethylsilyl protecting group) may be deprotected by    reaction with a source of fluoride ions, e.g. by employing the    reagent tetrabutylammonium fluoride (TBAF);-   (xi) aromatic nitration reactions (for instance which may be    performed on compounds corresponding to compounds of formula X, but    in which the —NH₂ group is replaced with a —NO₂ group; subsequent    conversion of the nitro group may take place separately—see (xii)    below); e.g. by reaction in the presence of nitric acid at low    temperature, followed by addition of conc. H₂SO₄);-   (xii) reductions of nitro groups to amino groups under standard    conditions, e.g. iron-based reduction), which may be followed by an    acylation reaction (see (ix) above) or a reductive amination    (see (iv) above).

The substituents R¹, R^(2a), R^(2b), R^(2c), R³, Z, X and Y (orsubstituents on the main core structure, including substituents on ringA/B) in final compounds of the invention or relevant intermediates maybe modified one or more times, after or during the processes describedabove by way of methods that are well known to those skilled in the art.Examples of such methods include substitutions, reductions, oxidations,alkylations, acylations, hydrolyses, esterifications, etherifications,halogenations or nitrations. Such reactions may result in the formationof a symmetric or asymmetric final compound of the invention orintermediate. The precursor groups can be changed to a different suchgroup, or to the groups defined in formula I, at any time during thereaction sequence. For example, in cases in which there is a —CO₂Hpresent, the skilled person will appreciate that at any stage during thesynthesis (e.g. the final step), the relevant ester group may behydrolysed to form a carboxylic acid functional group.

Compounds of the invention bearing a carboxyester functional group maybe converted into a variety of derivatives according to methods wellknown in the art to convert carboxyester groups into carboxamides,N-substituted carboxamides, N,N-disubstituted carboxamides, carboxylicacids, and the like. The operative conditions are those widely known inthe art and may comprise, for instance in the conversion of acarboxyester group into a carboxamide group, the reaction with ammoniaor ammonium hydroxide in the presence of a suitable solvent such as alower alcohol, dimethylformamide or a mixture thereof; preferably thereaction is carried out with ammonium hydroxide in amethanol/dimethylformamide mixture, at a temperature ranging from about50° C. to about 100° C. Analogous operative conditions apply in thepreparation of N-substituted or N,N-disubstituted carboxamides wherein asuitable primary or secondary amine is used in place of ammonia orammonium hydroxide. Likewise, carboxyester groups may be converted intocarboxylic acid derivatives through basic or acidic hydrolysisconditions, widely known in the art. Further, amino derivatives ofcompounds of the invention may easily be converted into thecorresponding carbamate, carboxamido or ureido derivatives.

Compounds of the invention may be isolated from their reaction mixturesusing conventional techniques (e.g. recrystallisations).

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter. Forexample, protected compounds/intermediates described herein may beconverted chemically to unprotected compounds using standarddeprotection techniques.

The type of chemistry involved will dictate the need, and type, ofprotecting groups as well as the sequence for accomplishing thesynthesis.

The use of protecting groups is fully described in “Protective Groups inOrganic Synthesis”, 3^(rd) edition, T. W. Greene & P. G. M. Wutz,Wiley-Interscience (1999).

Medical and Pharmaceutical Uses

Compounds of the invention are indicated as pharmaceuticals. Accordingto a further aspect of the invention there is provided a compound of theinvention, for use as a pharmaceutical.

For the avoidance of doubt, although compounds of the invention maypossess pharmacological activity as such, certainpharmaceutically-acceptable (e.g. “protected”) derivatives of compoundsof the invention may exist or be prepared which may not possess suchactivity, but may be administered parenterally or orally and thereafterbe metabolised in the body to form compounds of the invention. Suchcompounds (which may possess some pharmacological activity, providedthat such activity is appreciably lower than that of the “active”compounds to which they are metabolised) may therefore be described as“prodrugs” of compounds of the invention.

A “prodrug of a compound of the invention” is as hereinbefore defined,including compounds that form a compound of the invention, in anexperimentally-detectable amount, within a predetermined time (e.g.about 1 hour), following oral or parenteral administration. All prodrugsof the compounds of the invention are included within the scope of theinvention.

Furthermore, certain compounds of the invention may possess no orminimal pharmacological activity as such, but may be administeredparenterally or orally, and thereafter be metabolised in the body toform compounds of the invention that possess pharmacological activity assuch. Such compounds (which also includes compounds that may possesssome pharmacological activity, but that activity is appreciably lowerthan that of the “active” compounds of the invention to which they aremetabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possesspharmacological activity, and/or are metabolised in the body followingoral or parenteral administration to form compounds which possesspharmacological activity.

Compounds of the invention may inhibit protein or lipid kinases, such asa PI3 kinase (especially a class I PI3K), or a PIM family kinase (e.g.PIM-1, PIM-2 and/or PIM-3), for example as may be shown in the testsdescribed below (for example, the test for PI3Kα and PIM inhibitiondescribed below) and/or in tests known to the skilled person. Thecompounds of the invention may also inhibit mTOR. Thus, the compounds ofthe invention may be useful in the treatment of those disorders in anindividual in which the inhibition of such protein or lipid kinases(e.g. PI3K, particularly class I PI3K, mTOR and/or a PIM family kinase,e.g. PIM-1, PIM-2 or PIM-3) is desired and/or required (for instancecompounds of the invention may inhibit PI3K, particularly class I PI3Kand, optionally, may also inhibit either (or both of) mTOR and PIM).Hence, certain compounds of the invention may be “dual” (e.g. PI3K andmTOR; PI3K and PIM; or mTOR and PIM) inhibitors. Further, certaincompounds of the invention may be “triple” (e.g. PI3K, PIM and mTOR)inhibitors.

The term “inhibit” may refer to any measurable reduction and/orprevention of catalytic kinase (e.g. PI3K, particularly class I PI3K,mTOR and/or PIM) activity. The reduction and/or prevention of kinaseactivity may be measured by comparing the kinase activity in a samplecontaining a compound of the invention and an equivalent sample ofkinase (e.g. PI3K, particularly class I PI3K, mTOR and/or PIM) in theabsence of a compound of the invention, as would be apparent to thoseskilled in the art. The measurable change may be objective (e.g.measurable by some test or marker, for example in an in vitro or in vivoassay or test, such as one described hereinafter, or otherwise anothersuitable assay or test known to those skilled in the art) or subjective(e.g. the subject gives an indication of or feels an effect).

Compounds of the invention may be found to exhibit 50% inhibition of aprotein or lipid kinase (e.g. PI3K, such as class I PI3K, mTOR and/orPIM) at a concentration of 100 μM or below (for example at aconcentration of below 50 μM, or even below 10 μM, such as below 1 μM),when tested in an assay (or other test), for example as describedhereinafter, or otherwise another suitable assay or test known to theskilled person.

Compounds of the invention are thus expected to be useful in thetreatment of a disorder in which a protein or lipid kinase (e.g. PI3K,such as class I PI3K, mTOR and/or PIM) is known to play a role and whichare characterised by or associated with an overall elevated activity ofthat kinase (due to, for example, increased amount of the kinase orincreased catalytic activity of the kinase). Hence, compounds of theinvention are expected to be useful in the treatment of adisease/disorder arising from abnormal cell growth, function orbehaviour associated with the protein or lipid kinase (e.g. PI3K, suchas class I PI3K, mTOR and/or PIM). Such conditions/disorders includecancer, immune disorders, cardiovascular diseases, viral infections,inflammation, metabolism/endocrine function disorders and neurologicaldisorders.

Compounds of the invention (alone or in combination with another active)may be shown to be active e.g. in the biochemical assays describedherein, may be shown to have predictive activity based on e.g. thephosphorylation assay described herein, and/or may reduce the rate ofcell proliferation e.g. as may be shown in the cell proliferation assaysdescribed herein (for instance using cancer cell lines (e.g. knowncommercially available ones), such as those described herein or othersthat are known and publically available).

The disorders/conditions that the compounds of the invention may beuseful in treating hence includes cancer (such as lymphomas, solidtumours or a cancer as described hereinafter), obstructive airwaysdiseases, allergic diseases, inflammatory diseases (such as asthma,allergy and Crohn's disease), immunosuppression (such as transplantationrejection and autoimmune diseases), disorders commonly connected withorgan transplantation, AIDS-related diseases and other associateddiseases. Other associated diseases that may be mentioned (particularlydue to the key role of kinases in the regulation of cellularproliferation) include other cell proliferative disorders and/ornon-malignant diseases, such as benign prostate hyperplasia, familialadenomatosis, polyposis, neuro-fibromatosis, psoriasis, bone disorders,atherosclerosis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis andpost-surgical stenosis and restenosis. Other disease states that may bementioned include cardiovascular disease, stroke, diabetes,hepatomegaly, Alzheimer's disease, cystic fibrosis, hormone-relateddiseases, immunodeficiency disorders, destructive bone disorders,infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukaemia,liver disease, pathologic immune conditions involving T cell activation,CNS disorders and pulmonary artery hypertension (PAH).

As stated above, the compounds of the invention may be useful in thetreatment of cancer. More, specifically, the compounds of the inventionmay therefore be useful in the treatment of a variety of cancerincluding, but not limited to: carcinoma such as cancer of the bladder,breast, colon, kidney, liver, lung (including non-small cell cancer andsmall cell lung cancer), esophagus, gall-bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, skin, squamous cell carcinoma,testis, genitourinary tract, larynx, glioblastoma, neuroblastoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-smallcell lung carcinoma, small cell lung carcinoma, lung adenocarcinoma,bone, adenoma, adenocarcinoma, follicular carcinoma, undifferentiatedcarcinoma, papilliary carcinoma, seminona, melanoma, sarcoma, bladdercarcinoma, liver carcinoma and biliary passages, kidney carcinoma,myeloid disorders, lymphoid disorders, hairy cells, buccal cavity andpharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukaemia; hematopoietic tumors of lymphoid lineage,including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma;hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia; tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; tumors of the central and peripheral nervous system,including astrocytoma, neuroblastoma, glioma and schwannomas; and othertumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma,xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer andKaposi's sarcoma.

Further, the protein or lipid kinases (e.g. PI3K, such as class I PI3K,mTOR and/or PIM) may also be implicated in the multiplication of virusesand parasites. They may also play a major role in the pathogenesis anddevelopment of neurodegenerative disorders. Hence, compounds of theinvention may also be useful in the treatment of viral conditions,parasitic conditions, as well as neurodegenerative disorders.

Compounds of the invention are indicated both in the therapeutic and/orprophylactic treatment of the above-mentioned conditions.

According to a further aspect of the present invention, there isprovided a method of treatment of a disease (e.g. cancer or anotherdisease as mentioned herein) which is associated with the inhibition ofprotein or lipid kinase (e.g. PI3K, such as class I PI3K, mTOR and/orPIM) is desired and/or required (for example, a method of treatment of adisease/disorder arising from abnormal cell growth, function orbehaviour associated with protein or lipid kinases, e.g. PI3K, such asclass I PI3K, mTOR and/or PIM), which method comprises administration ofa therapeutically effective amount of a compound of the invention, ashereinbefore defined, to a patient suffering from, or susceptible to,such a condition.

“Patients” include mammalian (including human) patients. Hence, themethod of treatment discussed above may include the treatment of a humanor animal body.

The term “effective amount” refers to an amount of a compound, whichconfers a therapeutic effect on the treated patient. The effect may beobjective (e.g. measurable by some test or marker) or subjective (e.g.the subject gives an indication of or feels an effect).

Compounds of the invention may be administered orally, intravenously,subcutaneously, buccally, rectally, dermally, nasally, tracheally,bronchially, sublingually, by any other parenteral route or viainhalation, in a pharmaceutically acceptable dosage form.

Compounds of the invention may be administered alone, but are preferablyadministered by way of known pharmaceutical formulations, includingtablets, capsules or elixirs for oral administration, suppositories forrectal administration, sterile solutions or suspensions for parenteralor intramuscular administration, and the like. The type ofpharmaceutical formulation may be selected with due regard to theintended route of administration and standard pharmaceutical practice.Such pharmaceutically acceptable carriers may be chemically inert to theactive compounds and may have no detrimental side effects or toxicityunder the conditions of use.

Such formulations may be prepared in accordance with standard and/oraccepted pharmaceutical practice. Otherwise, the preparation of suitableformulations may be achieved non-inventively by the skilled person usingroutine techniques and/or in accordance with standard and/or acceptedpharmaceutical practice.

According to a further aspect of the invention there is thus provided apharmaceutical formulation including a compound of the invention, ashereinbefore defined, in admixture with a pharmaceutically acceptableadjuvant, diluent and/or carrier.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient ispresent in at least 1% (or at least 10%, at least 30% or at least 50%)by weight. That is, the ratio of active ingredient to the othercomponents (i.e. the addition of adjuvant, diluent and carrier) of thepharmaceutical composition is at least 1:99 (or at least 10:90, at least30:70 or at least 50:50) by weight.

The amount of compound of the invention in the formulation will dependon the severity of the condition, and on the patient, to be treated, aswell as the compound(s) which is/are employed, but may be determinednon-inventively by the skilled person.

The invention further provides a process for the preparation of apharmaceutical formulation, as hereinbefore defined, which processcomprises bringing into association a compound of the invention, ashereinbefore defined, or a pharmaceutically acceptable ester, amide,solvate or salt thereof with a pharmaceutically-acceptable adjuvant,diluent or carrier.

Compounds of the invention may also be combined with other therapeuticagents that are inhibitors of protein or lipid kinases (e.g. PI3K (suchas class I PI3K), mTOR, Flt3, a PIM family kinase (e.g. PIM-1, PIM-2 orPIM-3), EGFR and/or MEK) and/or useful in the treatment of a cancerand/or a proliferative disease. Compounds of the invention may also becombined with other therapies (e.g. radiation).

For instance, compounds of the invention may be combined with one ormore treatments independently selected from surgery, one or moreanti-cancer/anti-neoplastic/anti-tumoral agent, one or more hormonetherapies, one or more antibodies, one or more immunotherapies,radioactive iodine therapy, and radiation.

More specifically, compounds of the invention may be combined with anagent that modulates the Ras/Raf/Mek pathway (e.g. an inhibitor of MEK),the Jak/Stat pathway (e.g. an inhibitor of Jak), the PI3K/Akt pathway(e.g. an inhibitor of Akt), the DNA damage response mechanism (e.g. aninhibitor of ATM or ATR) or the stress signaling pathway (an inhibitorof p38 or NF-KB).

For instance, compounds of the invention may be combined with:

-   -   (i) a targeted kinase inhibitor;    -   (ii) a receptor tyrosine kinase (RTK) inhibitor;    -   (iii) a PIM family kinase inhibitor, such as SGI-1776;    -   (iv) an Flt-3 inhibitor;    -   (v) an EGFR or HER2 inhibitor, such as lapatanib;    -   (vi) a therapeutic monoclonal antibody, such as the HER2        inhibitor trastuzumab;    -   (vii) a MEK inhibitor, such as PD-0325901;    -   (vii) a BRaf inhibitor, such as GDC-0879;    -   (viii) an anthracyclin, such as doxorubicin;    -   (ix) a taxane, such as paclitaxel or, particularly, docetaxel;    -   (x) a platin, such as carboplatin or, particularly, cisplatin;    -   (xi) a nucleotide analog, such as 5-fluorouracil (5-FU) or        gemcitabine);    -   (xii) an alkylating agent, such as temozolomide;    -   (xiii) a hormone therapeutic agent, such as an estrogen receptor        antagonist e.g. tamoxifen;    -   (xiv) an anti-tumour compound that has potential        radiosensitising and/or chemosensitising effects, such as        chloroquine;    -   (xv) an mTOR inhibitor, such as rapamycin;    -   (xvi) an Akt or PI3-K inhibitor, such as GDC-0941;    -   (xvii) a JAK inhibitor;    -   (xviii) an agent that modulates the DNA damage response        mechanism and/or the stress signaling pathway, e.g. an inhibitor        of ATM or ATR, an inhibitor of p38 and/or NF-KB; and/or    -   (xix) a BCL-2 family inhibitor, such as AB5-737.

According to a further aspect of the invention, there is provided acombination product comprising:

-   (A) a compound of the invention, as hereinbefore defined; and-   (B) another therapeutic agent that is useful in the treatment of    cancer and/or a proliferative disease,

wherein each of components (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compoundof the invention in conjunction with the other therapeutic agent, andmay thus be presented either as separate formulations, wherein at leastone of those formulations comprises a compound of the invention, and atleast one comprises the other therapeutic agent, or may be presented(i.e. formulated) as a combined preparation (i.e. presented as a singleformulation including a compound of the invention and the othertherapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention,as hereinbefore defined, another therapeutic agent that is useful in thetreatment of cancer and/or a proliferative disease, and apharmaceutically-acceptable adjuvant, diluent or carrier; and

(2) a kit of parts comprising components:

-   (a) a pharmaceutical formulation including a compound of the    invention, as hereinbefore defined, in admixture with a    pharmaceutically-acceptable adjuvant, diluent or carrier; and-   (b) a pharmaceutical formulation including another therapeutic agent    that is useful in the treatment of cancer and/or a proliferative    disease in admixture with a pharmaceutically-acceptable adjuvant,    diluent or carrier,

which components (a) and (b) are each provided in a form that issuitable for administration in conjunction with the other.

In a particularly preferred aspect of the invention, compounds of theinvention may be combined with other therapeutic agents (e.g.chemotherapeutic agents) for use as medicaments (e.g. for use in thetreatment of a disease or condition as mentioned herein, such as one inwhich the inhibition of growth of cancer cells are required and/ordesired e.g. for treating hyperproliferative disorders such as cancer(e.g. specific cancers that may be mentioned herein, e.g. in theexamples) in mammals, especially humans). Such active ingredients incombinations may act in synergy.

In particular, compounds of the invention may be combined with knownchemotherapeutic agents (as may be demonstrated by the examples, forinstance where a compound of the examples is employed in combination andinhibits cellular proliferation in vitro; in particular suchcombinations may be useful in treating lung and/or ovarian cancer), forinstance:

-   -   (i) a MEK inhibitor, such as PD-0325901;    -   (ii) an EGFR inhibitor, such as Lapatinib; and/or    -   (iii) docetaxel (Taxotere®, Sanofi-Aventis).

The MEK inhibitor PD-0325901 (CAS RN 391210-10-9, Pfizer) is asecond-generation, non-ATP competitive, allosteric MEK inhibitor for thepotential oral tablet treatment of cancer (U.S. Pat. Nos. 6,960,614;6,972,298; US 2004/1147478; US 2005/085550). Phase II clinical trialshave been conducted for the potential treatment of breast tumors, colontumors, and melanoma. PD-0325901 is named(R)—N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benz-amide,and has the structure:

Docetaxel (TAXOTERE®, Sanofi-Aventis) is used to treat breast, ovarian,and NSCLC cancers (U.S. Pat. Nos. 4,814,470; 5,438,072; 5,698,582;5,714,512; 5,750,561; Mangatal et al (1989) Tetrahedron 45:4177; Ringelet al (1991) J. Natl. Cancer Inst. 83:288; Bissery et al (1991) CancerRes. 51:4845; Herbst et al (2003) Cancer Treat. Rev. 29:407-415; Davieset al (2003) Expert. Opin. Pharmacother. 4:553-565). Docetaxel is namedas (2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-esterwith 5, 20-epoxy-1, 2, 4, 7, 10, 13-hexahydroxytax-11-en-9-one 4-acetate2-benzoate, trihydrate (U.S. Pat. No. 4,814,470; EP 253738; CAS Reg. No.114977-28-5) (or named as1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate2-benzoate13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate})and has the structure:

Lapatinib (TYKERB®, GW572016, Glaxo SmithKline) has been approved foruse in combination with capecitabine (XELODA®, Roche) for the treatmentof patients with advanced or metastatic breast cancer whose tumorsover-express HER2 (ErbB2) and who have received prior therapy includingan anthracycline, a taxane and trastuzumab. Lapatinib is anATP-competitive epidermal growth factor (EGFR) and HER2/neu (ErbB-2)dual tyrosine kinase inhibitor (U.S. Pat. Nos. 6,727,256; 6,713,485;7,109,333; 6,933,299; 7,084,147; 7,157,466; 7,141,576) which inhibitsreceptor autophosphorylation and activation by binding to the ATPbindingpocket of the EGFRIHER2 protein kinase domain. Lapatinib is named asN-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino)-methyl)furan-2-yl)quinazolin-4-amine(or alternatively named asN-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine),and has the structure:

The invention further provides a process for the preparation of acombination product as hereinbefore defined, which process comprisesbringing into association a compound of the invention, as hereinbeforedefined, or a pharmaceutically acceptable ester, amide, solvate or saltthereof with the other therapeutic agent that is useful in the treatmentof cancer and/or a proliferative disease, and at least onepharmaceutically-acceptable adjuvant, diluent or carrier.

For instance, compounds of the invention may be combined with achemotherapeutic agent. A “chemotherapeutic agent” is a biological(large molecule) or chemical (small molecule) compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkylatingagents, antimetabolites, spindle poison plant alkaloids,cytotoxic/antitumor antibiotics, topoisomerase inhibitors, proteins,antibodies, photosensitizers, and kinase inhibitors. Chemotherapeuticagents include compounds used in “targeted therapy” and non-targeted,conventional chemotherapy.

Examples of chemotherapeutic agents include those mentioned in e.g. WO2010/105008, for instance: dexamethasone, thioTEPA, doxorubicin,vincristine, rituximab, cyclophosphamide, prednisone, melphalan,lenalidomide, bortezomib, rapamycin, and cytarabine.

Examples of chemotherapeutic agents also include: erlotinib (TARCEVA®,Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®,Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin(cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin(CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers SquibbOncology), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide,CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), doxorubicin (ADRIAMYCIN®), Akti-1/2,HPPD, rapamycin, and lapatinib (TYKERB®, Glaxo SmithKline).

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (MEK inhibitor, Exelixis, WO2007/044515), ARRY-886 (MEK inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), ABT-869(multi-targeted inhibitor of VEGF and PDGF family receptor tyrosinekinases, Abbott Laboratories and Genentech), ABT-263 (Bc1-2/Bcl-xLinhibitor, Abbott Laboratories and Genentech), PTK787/ZK 222584(Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinicacid), Ionafamib (SARASAR™, SCH 66336, Schering Plough), sorafenib(NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca),irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson& Johnson), capecitabine (XELODA®, Roche), ABRAXANE™ (Cremophor-free),albumin-engineered nanoparticle formulations of paclitaxel (AmericanPharmaceutical Partners, Schaumberg, Ill.), vandetanib (rINN, ZD6474,ZACTIMA®, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271; Sugen),temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline),canfosfamide (TELCYTA®, Telik), thioTepa and cyclosphosphamide(CYTOXAN®, NEOSAR®); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma II, calicheamicin omega II,dynemicin, dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; antiadrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; tiaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thioTepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such asretinoic acid; and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)antihormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipidkinase inhibitors; (vi) antisense oligonucleotides, particularly thosewhich inhibit expression of genes in signaling pathways implicated inaberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, suchas oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKN® rIL-2; topoisomerase 1 inhibitors suchas LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTN®, Genentech); cetuximab (ERBITUX®, lmclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG™, rhuMab 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanised monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the PI3K inhibitors of theinvention include: alemtuzumab, apolizumab, aselizumab, atlizumab,bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, rolizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

By “bringing into association”, we mean that the two components arerendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

-   (i) provided as separate formulations (i.e. independently of one    another), which are subsequently brought together for use in    conjunction with each other in combination therapy; or-   (ii) packaged and presented together as separate components of a    “combination pack” for use in conjunction with each other in    combination therapy.

Depending on the disorder, and the patient, to be treated, as well asthe route of administration, compounds of the invention may beadministered at varying therapeutically effective doses to a patient inneed thereof. However, the dose administered to a mammal, particularly ahuman, in the context of the present invention should be sufficient toeffect a therapeutic response in the mammal over a reasonable timeframe.One skilled in the art will recognize that the selection of the exactdose and composition and the most appropriate delivery regimen will alsobe influenced by inter alia the pharmacological properties of theformulation, the nature and severity of the condition being treated, andthe physical condition and mental acuity of the recipient, as well asthe potency of the specific compound, the age, condition, body weight,sex and response of the patient to be treated, and the stage/severity ofthe disease.

Administration may be continuous or intermittent (e.g. by bolusinjection). The dosage may also be determined by the timing andfrequency of administration. In the case of oral or parenteraladministration the dosage can vary from about 0.01 mg to about 1000 mgper day of a compound of the invention.

In any event, the medical practitioner, or other skilled person, will beable to determine routinely the actual dosage, which will be mostsuitable for an individual patient. The above-mentioned dosages areexemplary of the average case; there can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of the invention may have the advantage that they areeffective inhibitors of protein or lipid kinases (e.g. PI3K, such asclass I PI3K, mTOR and/or PIM). In an embodiment, compounds of theinvention may have the advantage that they are both PI3K (e.g. class IPI3K, such as PI3Kα) inhibitors and mTOR inhibitors, i.e. they mayexhibit dual kinase inhibition. In a further embodiment, compounds ofthe invention may have the advantage that they are PIM inhibitors andare also either PI3K (e.g. class I PI3K, such as PI3Kα) inhibitors ormTOR inhibitors, i.e. they may exhibit dual kinase inhibition. In a yetfurther embodiment, compounds of the invention may have the advantagethat they are PI3K (e.g. class I PI3K, such as PI3Kα) inhibitors, mTORinhibitors and PIM inhibitors, i.e. they may exhibit triple kinaseinhibition.

Compounds of the invention may also have the advantage that they may bemore efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile (e.g. higheroral bioavailability and/or lower clearance) than, and/or have otheruseful pharmacological, physical, or chemical properties over, compoundsknown in the prior art, whether for use in the above-stated indicationsor otherwise.

Pharmacokinetic data for a selection of the compounds of the inventionare shown in Table 4. These data demonstrate that the macrocycliccompounds are stable under physiological conditions. Without wishing tobe bound by theory, it is believed that the activity that is observedfor the compounds of the invention is associated with the compounds intheir macrocyclic forms, as opposed to in ring-open forms.

As stated hereinbefore, compounds of the invention may have theadvantage that they may exhibit triple (e.g. dual) kinase inhibitoryactivity (e.g. may act as inhibitors of combinations of PI3K (suchPI3Kα), mTOR and PIM (e.g. PI3K (such PI3Kα) and mTOR). In this respect,advantageously, compounds of the invention may be considered asmulti-targeted kinase inhibitors. Compounds of the invention thatexhibit single selectivity for a kinase may have the additional benefitthat they exhibit less side effects, whereas compounds of the inventionthat exhibit multiple kinase selectivity may have the additional benefitthat they exhibit better potency and/or efficacy.

To date, clinical development of PI3K and dual PI3K/mTOR inhibitors haveshown moderate activities, suggesting that either morepotent/efficacious inhibitors are required or that inhibition ofmultiple targets or even pathways might be required for effectivetreatments (see e.g. Bunney, Tom D., Katan, Matilda, Phosphoinositidesignalling in cancer: beyond PI3K and PTEN, Nature Reviews Cancer(2010), 10(5), 342-352; Cleary, James M. and Shapiro, Geoffrey I.,Development of phosphoinositide-3 kinase pathway inhibitors for advancedcancer, Current Oncology Report (2010), 12, 87-94; and van der Heijden,Michiel S. and Bernards, Rene; Inhibition of the PI3K Pathway: Hope WeCan Believe in? Clinical Cancer Research (2010), 16, 3094-3099).

Advantageously, the compounds of the invention may have the benefit thatthey inhibit multiple targets (or even multiple pathways). For instance,in addition to being inhibitors of PI3K, mTOR and PIM (e.g. PI3K (e.gPI3Kα) and mTOR), they may also be effective inhibitors of other proteinor lipid kinases (as may be demonstrated by known tests). In thisrespect, compounds of the invention may be considered to have animproved kinase inhibition cross-reactivity profile, e.g. by beingselective against multiple kinases of therapeutic interest, for instancecompared to compounds known in the prior art. They may have advantagesin the clinic.

Compounds of the invention may combine dual PI3K/mTOR activity(optionally together with PIM activity) with activity on other keykinases (indeed, combination products covering this spectrum of kinasesare currently being evaluated as mentioned above), thereby allowingsingle-agent administration (or, potentially, combination products withreduced dosages) and providing the associated benefits, e.g. reducingthe risk of drug-drug interactions, etc.

Compounds of the invention may be beneficial as they are medicamentswith targeted therapy, i.e. which target a particular molecular entityby inferring or inhibiting it (e.g. in this case by inhibiting one ormore protein or lipid kinases as hereinbefore described). Compounds ofthe invention may therefore also have the benefit that they have a neweffect (for instance as compared to known compounds in the prior art),for instance, the new effect may be a particular mode of action oranother effect resultant of the targeted therapy. Targeted therapies maybe beneficial as they may have the desired effect (e.g. reduce cancer,by reducing tumor growth or carcinogenesis) but may also have theadvantage of reducing side effects (e.g. by preventing the killing ofnormal cells, as may occur using e.g. chemotherapy).

Furthermore, compounds of the invention may selectively targetparticular protein or lipid kinases (e.g. the ones described herein)compared to other known protein or lipid kinases. Accordingly, compoundsof the invention may have the advantage that certain, specific, cancersmay be treated selectively, which selective treatment may also have theeffect of reducing side effects.

EXAMPLES/BIOLOGICAL TESTS

Determination of PI3 and PIM kinase activity of compounds of theinvention (such as those exemplified) is possible by a number of directand indirect detection methods. Certain exemplary compounds describedherein were prepared, characterized, and assayed for their PI3Kα, PIMand mTOR enzymatic activities using the methods described herein. Thecompounds may also be tested in cell-based assays.

PI3K Activity Assay

The kinase activity was measured by using the commercial ADP Hunter™Plus assay available from DiscoveR_(x) (#33-016), which is a homogeneousassay to measure the accumulation of ADP, a universal product of kinaseactivity. The enzyme, PI3K (p110α/p85α was purchased from CarnaBiosciences (#07CBS-0402A). The assay was done following themanufacturer recommendations with slight modifications: Mainly thekinase buffer was replace by 50 mM HEPES, pH 7.5, 3 mM MgCl₂, 100 mMNaCl, 1 mM EGTA, 0.04% CHAPS, 2 mM TCEP and 0.01 mg/ml BGG. The PI3K wasassayed in a titration experiment to determine the optimal proteinconcentration for the inhibition assay. To calculate the IC₅₀ of theETP-compounds, serial 1:5 dilutions of the compounds were added to theenzyme at a fixed concentration (2.5 μg/ml). The enzyme was preincubatedwith the inhibitor and 30 μM PIP₂ substrate (P9763, Sigma) for 5 min andthen ATP was added to a final 50 μM concentration. Reaction was carriedout for 1 hour at 25° C. Reagent A and B were sequentially added to thewells and plates were incubated for 30 min at 37° C. Fluorescence countswere read in a Victor instrument (Perkin Elmer) with the recommendedsettings (544 and 580 nm as excitation and emission wavelengths,respectively). Values were normalized against the control activityincluded for each enzyme (i.e., 100% PI3 kinase activity, withoutcompound). These values were plotted against the inhibitor concentrationand were fit to a sigmoid dose-response curve by using the Graphadsoftware.

mTOR Assay

The enzymatic mTOR activity was measured using a LanthaScreen™ kinaseactivity assay (Invitrogen). The enzyme was purchased from Invitrogen(PV4754), as well as the GFP-labeled substrate (4EBP1-GFP; PV4759) andthe Tb-anti-p4EBP1(pThr46) antibody (PV4757). The assay was performed in50 mM HEPES buffer, pH 7.5, containing 1.5 mM MnCl₂, 10 mM MgCl₂, 1 mMEGTA, 2.5 mM DTT and 0.01% Tween-20. The concentration of the assaycomponents were the following: 0.24 nM mTOR kinase, 400 nM 4EBP1-GFP, 10mM ATP and serial dilutions of the compound (inhibitor) to be evaluated.After 1 h incubation at room temperature, 20 mM EDTA was used to stopthe reaction and terbium-labeled antibody (4 nM) added to detectphosphorylated product. The antibody associates with the phosphorylatedproduct resulting in an increased TR-FRET value. The TR-FRET value (adimensionless number) was calculated as the ratio of the acceptor signal(GFP, emission at 520 nm) to the donor signal (terbium, emission at 495nm). Values were plotted against the inhibitor concentration and fittedto a sigmoid dose-response curve using GraphPad software.

PIM-1 Biochemical Assay

The biochemical assay to measure PIM-1 activity relies on the ADP Hunterassay kit (DiscoveRx Corp., Cat. #90-0077), that determines the amountof ADP as direct product of the kinase enzyme activity.

The enzyme has been expressed and purified in-house as a recombinanthuman protein with a C-terminal histidine tag. The protein is active andstable.

Assay conditions were as indicated by the kit manufacturers with thefollowing adaptations for the kinase activity step:

-   -   Kinase assay buffer and assay volume stay as recommended (15 mM        HEPES, pH 7.4, 20 mM NaCl, 1 mM EGTA, 0.02% Tween 20, 10 mM        MgCl₂ and 0.1 mg/ml bovine γ-globulins/75 μl assay volume)    -   Incubation time and temperature: 60 min at 30° C.    -   PIM-1 concentration: 50 pg/μl    -   ATP concentration: 100 μM    -   PIM-1 substrate peptide: PIMtide (ARKRRRHPSGPPTA) (SEQIDNO. 1)    -   Peptide concentration: 60 μM    -   Positive control for kinase activity inhibition: 1-10 μM        Staurosporine    -   DMSO concentration have to stay below 2% during the kinase        reaction

Assays were performed in either 96 or 384-well plates. The final outcomeof the coupled reactions provided by the kit is the release of thefluorescent product Resorufin and has been measured with a multilabelHTS counter VICTOR V (PerkinElmer) using an excitation filter at 544 nmand an emission filter at 580 nm.

Pharmacokinetic

Experiments were done using BALB-c female mice, 10 weeks old. Compoundswere dissolved in selected vehicles at a concentration calculated inorder to administer the dose selected in 0.1 mL. Animals wereadministered by i.v and oral route (by gavage), and sacrificed atdifferent time points (n=3 at each time point). Time points were 0.08,0.25, 0.5, 1, 4 and 8 h for the i.v branch, and 0.08, 0.16, 0.25, 0.5,1, 4, 8 and 24 h for oral branch. Blood was collected and processed forplasma which was analyzed and quantified by means of tandem massspectrometry coupled with liquid chromatography. Pharmacokineticparameters were estimated by fitting the experimental data to acompartmental model using Winnonlin software for pharmacokineticanalysis.

Cellular Mode of Action

Cell culture: The cell lines are obtained from the American Type CultureCollection (ATCC). U2OS (human osteosarcoma) is cultured in Dulbecco'smodified Eagle's medium (DMEM). PC3 (human prostate carcinoma), MCF7(human breast cardinoma), HCT116 (human colon carcinoma), 768-0 (humanneuroblastoma), U251 (human glyoblastoma) are grown in RPMI. All mediaare supplemented with 10% fetal bovine serum (FBS) (Sigma) andantibiotics-antimycotics. Cells are maintained in a humidified incubatorat 37° C. with 5% CO₂ and passaged when confluent using trypsin/EDTA.

Cytotoxicity Assessment

Cell viability in the presence of test compounds is measured by theCellTiter-Glo® Luminescent Cell Viability Assay, commercially availablefrom Promega Corp., Madison, Wis. This homogeneous assay method is basedon the recombinant expression of Coleoptera luciferase (U.S. Pat. Nos.5,583,024;5,674,713; 5,700,670) and determines the number of viablecells in culture based on quantitation of the ATP present, an indicatorof metabolically active cells (Crouch et al (1993) J. Immunol. Meth.160:81-88; U.S. Pat. No. 6,602,677). The CellTiterGlo® Assay wasconducted in 96 making it amenable to automated highthroughput screening(HTS) (Cree et al (1995) AntiCancer Drugs 6:398-404).

The homogeneous assay procedure involves adding the single reagent(CellTiter-Glut Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system detects as few as 15cells/well in a 96-well format in 10 minutes after adding reagent andmixing.

The homogeneous “add-mix-measure” format results in cell lysis andgeneration of a luminescent signal proportional to the amount of ATPpresent. The amount of ATP is directly proportional to the number ofcells present in culture. The CellTiter-Glo® Assay generates a“glow-type” luminescent signal, produced by the luciferase reaction,which has a half-life generally greater than five hours, depending oncell type and medium used. Viable cells are reflected in relativeluminescence units (RLU). The substrate, Beetle Luciferin, isoxidatively decarboxylated by recombinant firefly luciferase withconcomitant conversion of ATP to AMP and generation of photons. Theextended half-life eliminates the need to use reagent injectors andprovides flexibility for continuous or batch mode processing of multipleplates. This cell proliferation assay can be used with various multiwellformats, e.g. 96 or 384 well format. Data can be recorded by luminometeror CCD camera imaging device. The luminescence output is presented asrelative light units (RLU), measured over time.

PI3K Cellular Activity (ELISA Assay)

Activity is measured as endogenous levels of phospho-Akt1 (Ser473)protein. Osteosarcoma U2OS cells are plated in 96 Poly-D-Lysine coatingtissue culture plates (18.000 cells/well). After the treatment withserial dilutions of the compound during 3 h, the cells are fixeddirectly in the wells with 4% paraformaldehyde.

After fixing, individual wells go through the same series of steps usedfor a conventional immunoblot: including blocking with 5% BSA,incubation with 1/1000 of primary antibody-AKT (Ser 74) in PBScontaining 5% BSA at 4° C. overnight (Cell Signalling), washing andincubation with second antibody HRP-anti-mouse IgG for 1 h at RT(Amersham). After the addition of SuperSignal ELISA Femto maximumsensitivity chemiluminescent substrate (Pierce) the results are readusing a luminescence plate reader (Victor).

PIM-1 Cellular Assay (BAD S112 Phosphorylation Inhibition Assay)

The efficacy of compounds of the invention in inhibiting BADphosphorylation was measured by an In Cell ELISA. EC50 values wereestablished for the tested compounds.

Assay Conditions:

Cells: H1299 cells overexpressing PIM1 (H1299Pim1)

DMSO Plates: 96-well-Polystyrene, Untreated, Round-Bottom plates fromCostar (Cat #3797)

Cell Plates: 96-Flat bottom biocoated with Poly-D-Lysin plates with lidfrom Becton Dickinson (Cat#354651)

Cell Culture Medium: DMEM high glucose, 10% Fetal Bovine Serum, 2 mML-Glutamine, P/S

Antibodies: phosphor Bad S112 antibody from Cell Signaling (cat.#9291S), anti rabbit conjugated with peroxidise from Amersham(cat.#3619)

Reagent: SuperSignal ELISA femto from Pierce (cat.#1001110)

Procedure:

Cells were seeded in 15000 cells per 200 μl per well into 96-well platesand incubated for 16 h at 37° C., 5% CO₂. On day two, nine serial 1:2compound dilutions were made in DMSO in a 96-well plate. The compoundswere added to duplicate wells in 96-well cell plates using a FX BECKMANrobot (Beckman Coulter) and incubated at 37° C. with CO₂ atmosphere.After 4 hours, relative levels of Bad S112 phosphorylation were measuredin Cell ELISA using SuperSignal ELISA Femto substrate (Pierce) and readon VICTOR (Perkin Elmer). EC50 values were calculated using ActivityBasefrom IDBS.

EXAMPLES

The following Examples illustrate the invention.

Experimental Part

Hereinafter, the term “DCM” means dichloromethane, “MeOH” meansmethanol, “THF” means tetrahydrofuran, “DMF” means dimethylformamide,“DME” means 1,2-dimethoxyethane, “EtOAc” means ethyl acetate, “BOP”means (Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate, “HOAt” means 1-hydroxy-7-azabenzotriazole, “PyBOP”means (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate, “DMAP” means 4-dimethylaminopyridine, “HATU” meansO-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, “Pd(PPh₃)₄” meanstetrakis(triphenylphosphine)palladium, “PdCl₂(dppf)-DCM” means1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride,dichloromethane, “DIPEA” means diisopropylethylamine, “TFA” meanstrifluoroacetic acid, “min” means minutes, “h” means hours, “RT” meansroom temperature, “eq” means equivalents, “nBuOH” means n-butanol, “mw”means microwave.

General Procedure

NMR spectra were recorded in a Bruker Avance II 300 spectrometer andBruker Avance II 700 spectrometer fitted with 5 mm QXI 700 S4 inversephase, Z-gradient unit and variable temperature controller.

The HPLC measurements were performed using a HP 1100 from AgilentTechnologies comprising a pump (binary) with degasser, an autosampler, acolumn oven, a diode-array detector (DAD) and a column as specified inthe respective methods below. Flow from the column was split to a MSspectrometer. The MS detector was configured with an electrosprayionization source or API/APCI. Nitrogen was used as the nebulizer gas.Data acquisition was performed with ChemStation LC/MSD quad, software.

Method 1

Reversed phase HPLC was carried out on a Gemini-NX C18 (100×2.0 mm; 5um).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with0.1% formic acid. Gradient: 5% to 100% of B within 8 min at 50° C., DAD.

Method 2

Reversed phase HPLC was carried out on a Gemini-NX C18 (100×2.0 mm; 5um).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with0.1% formic acid. Gradient: 5% to 40% of B within 8 min at 50° C., DAD.

Method 3

Reversed phase HPLC was carried out on a Gemini-NX C18 (100×2.0 mm; 5um).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with0.1% formic acid. Gradient: 0% to 30% of B within 8 min at 50° C., DAD.

Method 4

Reversed phase HPLC was carried out on a Gemini C18 column (50×2 mm, 3urn).

Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with0.1% formic acid. Gradient: 10% to 95% of B within 4 min at 50° C., DAD.

Method 5

Reversed phase HPLC was carried out on a Gemini C18 column (50×2 mm, 3um). Solvent A: water with 0.1% formic acid; Solvent B: acetonitrilewith 0.1% formic acid. Gradient: 0% to 30% of B within 4 min at 50° C.,DAD.

“Found mass” refers to the most abundant isotope detected in theHPLC-MS.

The compound names given herein may be generated in accordance withIUPAC using the AutoNom naming program in MDL ISIS Draw.

Preparation of Intermediates

The synthesis of the some intermediates may have already been describedin international patent applications WO2009/040552, WO2008/150827 and WO2010/112874.

Synthesis of Intermediate I-01

To a solution of (5-amino-6-methoxypyridin-3-yl)boronic acid pinacolester (1.0 g, 3.99 mmol) in pyridine (13.3 mL) at 0° C. was added3-(chlorosulfonyl)benzoic acid (1.11 g, 4.79 mmol). The reaction mixturewas stirred at 0° C. for 3 h. The mixture was concentrated and theresidue was purified by column chromatography (Biotage, cHex:EtOAc 100:0to 0:100) to give Intermediate I-01 (1.15 g, 82%).

Synthesis of Intermediate 1-02

To a mixture of 5-bromo-2-chloro-3-nitropyridine (5 g, 21.06 mmol) in2-propanol (60 mL) was added DBU (15.7 mL, 105.3 mmol). The reactionmixture was stirred at 50° C. for 17 h. After cooling to RT, 1N HCl wasadded and the mixture was concentrated under reduced pressure. Aqueouslayer was extracted with EtOAc (×4). Combined organic layers were washedwith 1N HCl, dried, filtered and evaporated. The residue was purified onsilica gel (Biotage, cHex/EtOAc 100:0 to 90:10) to give Intermediate1-02 (974 mg, 18%).

Synthesis of Intermediate 1-03

To a solution of Intermediate I-02 (978 mg, 3.75 mmol) in a 4:1 mixtureof acetic acid/water (10 mL) was added Iron (628 mg, 11.24 mmol). Thereaction mixture was stirred at RT for 4 h. EtOAc was added, and themixture was filtered through a plug of celite. The filtrate was basifiedby addition of 5N NaOH. The mixture was extracted with EtOAc (×3) andthe combined organic layers were dried, filtered and evaporated. Theresidue was purified on silica gel (Biotage, cHex/EtOAc 100:0, 80:20) toobtain Intermediate I-03 (338 mg, 39%).

Synthesis of Intermediate I-04

To a mixture of Intermediate I-03 (338 mg, 1.46 mmol),bis(pinacolato)diboron (446 mg, 1.75 mmol) and KOAc (431 mg, 4.39 mmol)in 1,4-dioxane/DMF (2 mL/0.2 mL) was added PdCl₂(dppf). DCM (121 mg,0.15 mmol). The reaction mixture was heated under microwave conditionsat 150° C. for 10 min. On cooling, the mixture was filtered through acolumn of silica gel (isolute Si II, 5 g) with a pad of celite on itstop eluting with EtOAc. The filtrate was evaporated and the residue waspurified on silica gel (Biotage, cHex/EtOAc 90:10 to 0:100) to obtainIntermediate I-04 (169 mg, 42%).

Synthesis of Intermediate I-05

A mixture of methyl 3-aminothiophene-2-carboxylate (1 g, 6.362 mmol) andacetonitrile (0.50 mL, 9.542 mmol) in HCl (4M in 1,4-dioxane, 12.70 mL)was placed into a sealed tube and left under sonication at RT for 4 h.The reaction mixture was then heated at 100° C. for 16 h. More HCl (4Min 1,4-dioxane, 2 mL) and CH₃CN (0.25 mL) were added and the mixture washeated at 100° C. for 2 h. NaOH (5 N, 12 mL) was added and the mixturewas refluxed for 30 min. On cooling, H₂O was added and the mixture wasextracted with EtOAc. The combined organic layers were dried (Na₂SO₄),filtered and concentrated to give Intermediate I-05 (184 mg). Theaqueous layer was evaporated under vacuum and the residue was trituratedfrom H₂O to give Intermediate I-05 (463 mg) as a pale yellow solid.Total yield: 61%.

Synthesis of Intermediate I-06

To acetic anhydride (18 mL) at 0° C. was added dropwise formic acid (12mL) followed by the portionwise addition of methyl3-amino-4-methylthiophene-2-carboxylate (5 g, 29.2 mmol). The reactionmixture was stirred at RT for 18 h. The mixture was poured into asolution of Na₂CO₃ (30 g) in water (100 mL) at 0° C. The resulting whitesolid was filtered off, washed with water and dried to give IntermediateI-06 (4.69 g, 81%) as a white solid.

¹H NMR (300 MHz, DMSO) δ 9.85 (s, 1H), 8.24 (s, 1H), 7.55 (s, 1H), 3.76(s, 3H), 2.07 (s, 3H).

Synthesis of Intermediate I-07

A mixture of Intermediate I-06 (4.65 g, 23.25 mmol) and ammonium formate(10 g, 200 mmol) in formamide (6 mL) was heated at 160° C. for 18 h. Oncooling, the resulting solid was filtered, washed with acetone and driedto give Intermediate I-07 (3.85 g, 99%) as a white solid.

¹H NMR (300 MHz, DMSO) δ 8.18 (s, 1H), 7.81 (d, J=0.7 Hz, 1H), 2.31 (d,J=0.9 Hz, 3H).

Synthesis of Intermediate I-08

A mixture of methyl 3-aminothiophene-2-carboxylate (2 g, 12.72 mmol) andisobutyronitrile (1.71 mL, 19.08 mmol) in HCl (4M in 1,4-dioxane, 25 mL)was placed into a seated tube and left under sonication at RT for 4 h.The reaction mixture was then heated at 100° C. for 16 h. More HCl (4Min 1,4-dioxane, 4 mL) and isobutyronitrile (0.9 mL) were added and themixture was stirred at RT for 20 h. 5N NaOH (24 mL) was added and themixture was refluxed for 1 h. The solvent was evaporated and H₂O and 6NHCl were added to the residue. The resulting suspension was filtered offand washed with a lot of H₂O and Et₂O to give Intermediate I-08 (2.40 g,97%).

LC-MS: R_(t)=2.64 min, [M+H]⁺=195.0.

¹H NMR (300 MHz, CDCl₃) δ 11.76 (s, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.36(d, J=5.3 Hz, 1H), 3.09 (m, 1H), 1.43 (d, 6H).

Synthesis of Intermediate I-09

A solution of 5-cyano-4-methylthiophene-2-boronic acid (0.2 g, 1.20mmol) in 7N NH₃ in MeOH was hydrogenated in an H-cube apparatus (RaneyNickel, flow 1 mL/min, 50 bar, 50° C., recirculating mode) for 2 h 45min. Solvent was evaporated under reduced pressure to give IntermediateI-09 (164 mg, 80%).

Method A-1

Synthesis of Intermediate I-01

To a sealed tube charged with 6-Bromo-4-chloro-quinoline 1-00 (2.3 g,9.48 mmol) in 1,4-dioxane (75 ml),2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-ylamine (2.85 g, 11.38 mmol), K₂CO₃ (aq. sol. 1M) (40 ml) andtetrakis(triphenylphosphine)palladium(0) (1.096 g, 0.948 mmol) wereadded. The reaction mixture was heated at 100° C. for 1 h. The mixturewas concentrated and purified by flash chromatography in a Biotage usingcyclohexane-EtOAc gradient to give intermediate I-01 (2.2 g, Y: 81%).

Synthesis of Intermediate II-01

To a solution of 2-Bromo-5-iodo-imidazo[2,1-b]-1,3,4-thiadiazole (0.55g, 1.67 mmol) in 1,4-dioxane (9 mL),2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-ylamine (0.5 g, 2 mmol), Na₂CO₃ (aq. sol. 2M) (5 mL) and PdCl₂(PPh₃)₂ (117mg, 0.167 mmol) were added. The reaction mixture was heated (sand bath)in a sealed tube at 110° C. for 2.5 h. On cooling, water was added andthe suspension was filtered and rinsed with H₂O and Et₂O. The solid waspurified through a path of silica (EtOAc:DCM 10:90 to 50:50) to give theintermediate II-01 (2.16 g, Y: 23%) as a beige solid.

Synthesis of Intermediate III-02

To a solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (III-01) (0.5g, 2.151 mmol) in DME (10 mL) was added(5-amino-6-methoxypyridin-3-yl)boronic acid pinacol ester (538 mg, 2.151mmol), K₂CO₃ 2M (3.3 mL, 6.452 mmol) and PdCl₂(PPh₃)₂ (45 mg, 0.065mmol). The reaction mixture was heated in a sealed tube at 80° C. for 30min. 3-(N-Boc-aminomethyl)pyridine-5-boronic acid pinacol ester (719 mg,2.151 mmol) and PdCl₂(PPh₃)₂ (45 mg, 0.065 mmol) were added and themixture was heated at 80° C. for 22 h. On cooling, the mixture wasdiluted with EtOAc and washed with brine. The organic layer was dried,filtered and evaporated. The residue was purified by flashchromatography in a Biotage using MeOH:DCM 4:96 to 10:90 gradient togive intermediate III-02 (545 mg, 56%) as a yellow solid.

Synthesis of Intermediate IV-02

To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (IV-01) (450mg, 1.936 mmol) in 1,4-dioxane (8 mL) was added3-(N-Boc-aminomethyl)pyridine-5-boronic acid pinacol ester (679 mg,2.033 mmol), aq. Na₂CO₃ 2M (3 mL, 6 mmol) and PdCl₂(PPh₃)₂ (136 mg,0.194 mmol). The resulting mixture was heated at 80° C. in a sealed tubefor 8 h. On cooling, the mixture was diluted with DCM and water. Layerswere separated and the aqueous phase was extracted twice with DCM. Thecombined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (Biotage)using MeOH:DCM 0:100 to 20:80 as eluent to afford intermediate IV-02(525 mg, 75%).

Synthesis of Intermediate VIII-18

To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine VIII-01 (30 mg,0.101 mmol) in 1,2-dioxane (0.81 mL) was added 3-aminopyridine-5-boronicacid, pinacol ester (27 mg, 0.121 mmol), K₂CO₃ 1M (0.42 mL) andPd(PPh₃)₄ (12 mg, 0.010 mmol). The reaction mixture was heated at 100°C. for 1 h. Then 3-(N-Boc-aminomethyl)pyridine-5-boronic acid, pinacolester (50 mg, 0.142 mmol), K₂CO₃ 1M (0.42 mL) and Pd(PPh₃)₄ (12 mg,0.010 mmol) were added. The reaction mixture was heated at 100° C. for 1h. On cooling, the mixture was concentrated and the residue was purifiedby column chromatography (Biotage, cHex:EtOAc 100:0 to 0:100 andEtOAc:MeOH 100:0 to 80:20) to give intermediate VIII-18 (17 mg, 39%).

Method A-2

To a solution of the corresponding 2-methoxy-pyridin-3ylamineintermediate (1 eq.) in pyridine (10 mL/mmol) at 0° C. was added therequired sulfonyl chloride (1.2 eq.). The reaction mixture was stirredat 0° C. for 1 h, MeOH was added and the mixture was evaporated. Theresidue was purified either by flash chromatography in a Biotage usingMeOH:EtOAc gradient or by precipitation from MeOH to give the desiredsulfonilated product.

Synthesis of Intermediate IX-10

A mixture of Intermediate IX-09 (0.7 g, 1.507 mmol),3-chlorosulfonyl-benzoic acid (0.83 g, 3.773 mmol), pyridine (7 mL) andDCM (35 mL) was stirred at 40° C. overnight. Methanol (20 mL) was addedto the reaction mixture. The mixture was concentrated and diluted into20 mL of 1N NaOH at 0° C. The mixture was extracted with EtOAc. Theaqueous phase was adjusted to pH=3 by 1N HCl and extracted with EtOAc.The organic phase was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography to give Intermediate IX-10(0.4 g, yield: 41%).

Method A-3

In a sealed tube charged with the halogenated starting material (1 eq.)in 1,4-dioxane (10 mL/mmol), the corresponding boronic acid (1.2 eq.),K₂CO₃ (aq. sol. 1M) (3 eq.) and tetrakis(triphenylphosphine)palladium(0)(0.1 eq.) were added. The reaction mixture was heated at 100° C. for 1-2h. The mixture was concentrated and the crude was purified by flashchromatography in a Biotage using Cyclohexane/EtOAc followed byEtOAc/MeOH gradient to give the desired product.

Synthesis of Intermediate II-02

To a solution of intermediate II-01 (0.54 g, 1.44 mmol) in 1,4-dioxane(7.5 mL), 3-(n-boc-aminomethyl)pyridine-5-boronic acid pinacol ester(0.58 g, 1.73 mmol), Na₂CO₃ (aq. sol. 2M) (2.25 mL) and PdCl₂(PPh₃)₂(102 mg, 0.144 mmol) were added. The reaction mixture was heated (sandbath) in a sealed tube at 110° C. for 2 h. On cooling, water was addedand the suspension was filtered off and rinsed with H₂O and Et₂O to giveintermediate 3-05 (0.412 g, Y: 63%). The aqueous phase was neutralisedwith HCl 25% and extracted with DCM. The organic phase was separated,dried (Na₂SO₄), filtered and evaporated. The residue was purified byflash chromatography in a Biotage (MeOH:DCM 2:98 to 10:90) to giveintermediate II-02 (0.17 g, Y: 26%), global yield: 89%.

Synthesis of Intermediate VII-07

A mixture of intermediate VII-06 (3.76 g, 8.95 mmol),2-methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine(2.35 g, 9.40 mmol), Na₂CO₃ (1.9 g, 17.9 mmol), Pd(dppf)Cl₂ (0.36 g,0.45 mmol) in H₂O (8 mL) and DME (60 mL) was stirred at 120° C. under N₂overnight. The mixture was poured into ice water and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography to givethe intermediate VII-07 (3.48 g, 84%).

Synthesis of Intermediate VII-10

A mixture of intermediate VII-01 (0.50 g, 2.06 mmol),{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamicacid tert-butyl ester (0.73 g, 2.16 mmol), Pd(dppf)Cl₂ (84 mg, 0.10mmol), and Na₂CO₃ (0.65 g, 6.17 mmol) in DME (8 mL) and H₂O (2.5 mL) washeated under microwave irradiation at 140° C. for 40 min. The mixturewas poured into water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated. The residue waspurified by chromatography column on silica gel to give intermediateVII-10 (125 mg, 15%).

Synthesis of Intermediate VIII-09

To a mixture of Intermediate VIII-02 (2 g, 6.8 mmol),{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamicacid tert-butyl ester (2.2 g, 6.8 mmol) and K₂CO₃ (2.8 g, 20.4 mmol) indioxane (20 mL) and H₂O (10 mL) was added Pd(dppf)Cl₂ (0.5 g, 0.7 mmol)under N₂. The mixture was heated to 85° C. and stirred 2 h. The reactionmixture was cooled to RT, poured into water, and extracted with CH₂Cl₂(50 mL×4). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography to give Intermediate VIII-09 (1.7 g, 53%) as ayellow solid.

Synthesis of Intermediate XVII-03

A mixture of Intermediate XVII-02 (233 mg, 0.49 mmol),5-(Boc-aminomethyl)thiophene-2-boronic acid (159 mg, 0.62 mmol), K₃PO₄(178 mg, 0.80 mmol), tricyclohexylphosphine (28 mg, 0.11 mmol) andPd(dba)₂ (47 mg) in degassed dioxane (10 mL) and water (0.6 mL) washeated for 3 h at 120° C. under microwave irradiation. On cooling, themixture was evaporated and the residue was purified by columnchromatography (hexanes/EtOAc, 90:10 to 0:100) to give the esterintermediate as a brown solid (205 mg). By eluting the column withEtOAc/MeOH 80:20 the acid Intermediate XVII-03 was obtained (50 mg).

The ester (205 mg) was dissolved in EtOH (10 mL), the mixture was cooledto 0° C., 4N KOH (10 mL) was added and the mixture was stirred for 4 hat RT. The EtOH was carefully removed, water (5 mL) was added, and themixture was cooled to 0° C. Acetic acid was added until the solution hada pH of ˜4, and the resulting solid was filtered, washed with water anddried to give the acid as a grey solid (183 mg). Both collected acids(50 mg+183 mg) were combined and purified by column chromatography(EtOAc/MeOH, 100:0 to 80:20) to give Intermediate XVII-03 as a brownsolid (193 mg, 61%).

Method A-4

Synthesis of Intermediate I-03

In a sealed tube charged with intermediate I-02 (250 mg, 0.532 mmol) in1-methyl-2-pyrrolidinone (4.5 ml),4-(tert-butoxycarbonylaminomethyl)piperidine (238 mg, 1.064 mmol) wasadded. The reaction mixture was heated at 150° C. for 1 h. The mixturewas concentrated. The crude was purified by flash chromatography in aBiotage using Cyclohexane/AcOEt gradient followed by AcOEt/MeOH gradientto give intermediate I-03 (154 mg, Y: 45%).

Synthesis of Intermediate I-04

In a sealed tube charged with intermediate I-02 (260 mg, 0.553 mmol) in1-methyl-2-pyrrolidinone (3 ml), N-boc-1,4-diaminobutane (214 mg, 1.107mmol) was added. The reaction mixture was heated at 150° C. for 1.5 h.The mixture was concentrated. The crude was purified by flashchromatography in a Biotage using Cyclohexane/AcOEt gradient followed byAcOEt/MeOH gradient to give intermediate I-04 (137 mg, Y: 40%).

Synthesis of Intermediate VII-06

To a solution of intermediate VII-01 (2.08 g, 8.56 mmol) in ClCH₂CH₂CI(40 mL) was added 4-(tert-butoxycarbonylaminomethyl)piperidine (1.92 g,8.99 mmol) and Et₃N (1.73 g, 17.12 mmol) at 0° C. The mixture wasstirred at RT overnight. The mixture was poured into ice water andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, and concentrated to give the intermediate VII-06 (3.45 g,crude), which was used in the next step with no further treatment.

Synthesis of Intermediate VIII-12

To a solution of intermediate VIII-02 (0.6 g, 2.05 mmol) and Et₃N (0.62g, 0.15 mmol) in n-Butanol (30 mL) was added4-(tert-butoxycarbonylaminomethyl)piperidine (0.66 g, 3.08 mmol). Themixture was heated to reflux and stirred for 3 h. On cooling, thereaction mixture was concentrated. The residue was purified by columnchromatography to give Intermediate VIII-12 (0.8 g, 83%) as a yellowsolid.

Method A-5

Synthesis of Intermediates I-07 & I-08

To a solution of intermediate I-06 (620 mg, 0.966 mmol) in dioxane (8ml) at 0° C. was added dropwise a solution of HCl (4 N in water) (8 ml).The reaction mixture was stirred for 2 h. Additional amount of HCl (4 N)(8 ml) was added and the mixture was stirred at RT for 2 h. The reactionwas evaporated till dryness. The residue, mixture of intermediates I-07and I-08, was used in the next step without further purification.

Synthesis of Intermediates II-04 & II-05

To a solution of intermediate II-03 (80 mg, 0.125 mmol) in dioxane (1.25mL) was added HCl (4 M in dioxane) (1.25 mL). Two more additions of HCl(1 mL) were made and the mixture was finally stirred at RT over theweekend. The reaction was concentrated in vacuo and coevaporated withtoluene. The residue, mixture of intermediates II-04 and II-05, was usedin the next step without further purification.

Synthesis of Intermediate VIII-24

To a suspension of Intermediate VIII-04 (200 mg, 0.308 mmol) in1,4-dioxane (3 mL) was added HCl 4N in dioxane (3.85 mL, 15.415 mmol).The reaction mixture was heated in a pressure tube at 100° C. for 4 h.On cooling, the mixture was filtered and washed with Et₂O to giveIntermediate VIII-24 (200 mg, quant.) contaminated with aprox. 5% of themethoxy-derivative.

Method A-6

Synthesis of Intermediate II-10

To a suspension of the corresponding Boc-amino (1 eq.) in DCM (5mL/mmol) was added TFA (5 mL/mmol). The solution was stirred at RT for1-18 h. The mixture was concentrated and coevaporated with toluene threetimes to give the desired product as trifluoroacetic salt. It was usedin the next experiment without further purification. Quantitative yieldwas assumed.

Synthesis of Intermediate XIII-38

The corresponding acid (1 eq.) was suspended in DCE (5 mL/mmol), themixture cooled to 0° C. and TFA (5 mL/mmol) was added. The mixture wasstirred for 4 h at room temperature and the solvents were removed invacuo to give the desired compound as trifluoroacetic salt. It was usedin subsequent reactions without further purification. A quantitativeyield was assumed.

Method A-7

Synthesis of Intermediate II-08

To a solution of Intermediate II-07 (trifluoroacetic salt, raw material,290 mg, 0.436 mmol) in DCM (8 mL) and DMF (1 mL) was added DIPEA (0.38mL, 2.18 mmol), Boc-Gly-OH (153 mg, 0.871 mmol), BOP (385 mg, 0.871mmol) and DMAP (5 mg, 0.044 mmol). The mixture was stirred at RT for 2 hand evaporated. The residue was taken up in EtOAc and washed with H₂Oand HCl 1.2 M. The organic layer was dried, filtered and evaporated togive Intermediate II-08 (510 mg). It was used in the next experimentwith no further treatment. Quantitative yield was assumed.

Method A-8

Synthesis of Intermediate II-09

To a solution of Intermediate II-08 (raw material, 310 mg, 0.437 mmol)in MeOH (8 mL) was added LiOH.H₂O (184 mg, 4.37 mmol). The reactionmixture was stirred at RT for 8 h and more LiOH H₂O (184 mg) was added.The mixture was stirred overnight and evaporated to give IntermediateII-09. It was used in the next experiment with no further treatment.Quantitative yield was assumed.

Synthesis of Intermediate VIII-22

To a mixture of Intermediate VIII-21 (157 mg, 0.225 mmol) in1,4-dioxane/water (3:1, 4 mL) was added potassium carbonate. Thereaction was heated at 100° C. for 5 h. On cooling, the mixture wasevaporated, water was added, and the pH was adjusted to 5 with 1N HCl.The mixture was extracted with EtOAc. The aqueous layer was furtheracidified until pH 3 and extracted with 1:1 CHCl₃/^(i)PrOH. All theorganic layers were combined, dried and filtered to give IntermediateVIII-22 (127 mg, 83%).

Synthesis of Intermediate VIII-65

To a solution of Intermediate VIII-64 (275 mg, 0.41 mmol) in 1,4-dioxane(3 mL) was added 2M KOH (1 mL, 2 mmol). The reaction mixture was stirredat RT for 4.5 h. The mixture was partially evaporated under reducedpressure without heating. Water was added and pH was adjusted to pH 2with 2M HCl. The aqueous layer was extracted twice with EtOAc, dried,filtered and evaporated to afford Intermediate VIII-65 (248 mg, 92%).

Method A-9

Synthesis of Intermediate V-02

To a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine V-01 (1.58 g,4.64 mmol) in DCM (47 mL) was added benzenesulfonyl chloride (1.32 mL,10.22 mmol), tetrabutylammonium hydrogen sulfate (55% in water, 0.75 mL,1.16 mmol) and NaOH (50% aq., 14 mL). The reaction mixture was stirredat RT for 12 h. The mixture was quenched with brine and the aqueouslayer was extracted with DCM (2×20 mL). The combined organic layers weredried over Na₂SO₄, filtered and evaporated. Ice-cold methanol was addedto the residue and the mixture was stirred at 0° C. for 1 h. Thesuspension was filtered off and the solid was washed with ice-coldmethanol to afford Intermediate V-02 (1.72 g, 80%) as a pale yellowsolid.

Method A-10

Synthesis of Intermediate XII-01

A mixture of Intermediate I-05 (647 mg, 3.893 mmol) and POCl₃ (32 mL)was refluxed for 5 h. The reaction mixture was cooled down to RT andpoured very carefully into sat. Na₂CO₃. The aqueous layer was extractedwith EtOAc. The combined organic layers were dried (Na₂SO₄), filteredand evaporated to give Intermediate XII-01 (518 mg, 72%) as a pale brownsolid.

Synthesis of Intermediate XIII-01

A mixture of Intermediate 1-07 (4.85 g, 24.34 mmol) and POCl₃ (20 mL)was refluxed for 3 h. On cooling, the solvents were removed in vacuo,the residue was suspended in water and the suspension was cooled to 0°C. Aqueous saturated Na₂CO₃ was added dropwise at 0° C. up to pH˜8. Theresulting solid was filtered, washed with water and dried to giveIntermediate XIII-01 (1.1 g, 20%) as a white solid.

¹H NMR (300 MHz, DMSO) δ 9.01 (s, 1H), 8.19 (q, J=1.1 Hz, 1H), 2.39 (d,J=1.1 Hz, 3H).

Method A-11 Synthesis of Intermediate XII-02

To a mixture of Intermediate XII-01 (429 mg, 2.323 mmol) in THF (12 mL)was added LDA (1.8 M in THF/heptane/ethylbenzene, 1.55 mL, 2.788 mmol)at −78° C. After stirring at −78° C. for 1 h, a solution of I₂ (737 mg,2.904 mmol) in THF (2.6 mL) was slowly added. The reaction mixture wasstirred at −78° C. for 2 h. EtOAc was added to the mixture at −78° C.followed by the addition of H₂O. The aqueous layer was extracted withEtOAc and the combined organic layers were dried (Na₂SO₄), filtered andconcentrated. The residue was triturated from MeCN to give IntermediateXII-02 (515 mg, 71%) as a pale brown solid.

TABLE 1 Intermediates

Starting Yield No. R1 R2 Material Method % I-02

Cl I-01 A-2 54 I-05

Cl I-01 A-2 43 I-06

I-02 A-3 84 I-09

I-02 A-3 82 I-10

I-02 A-3 57 I-11

I-02 A-3 62 I-12

I-05 A-3 66 I-13

I-09 A-6 Quant. I-14

I-03 A-6 Quant. I-15

I-04 A-6 Quant. I-16

I-12 A-6 Quant. I-17

I-10 A-6 Quant. I-18

I-02 A-3 73 I-19

I-18 A-6 Quant. I-02

Cl I-00 A-1 Quant. I-20

I-02 A-1 88 I-21

I-20 A-6 Quant. I-22

I-02 A-4 64 I-23

I-22 A-6 Quant. I-24

I-05 A-3 65 I-25

I-24 A-6 Quant. I-26

I-01 A-1 83 I-27

I-26 A-2 31 I-28

I-27 A-6 Quant. I-29

Cl I-00 A-1 83 I-30

Cl I-29 A-2 47 I-31

I-30 A-1 90 I-32

I-31 A-6 Quant.

Starting Yield No. R1 R2 Material Method % II-03

II-02 A-2 45 II-06

II-02 A-2 20 II-07

II-06 A-6 Quant. II-10

II-09 A-6 Quant. II-11

II-01 A-3 53 II-12

II-11 A-2 44 II-13

II-12 A-6 Quant. II-14

II-01 A-3 26 II-15

II-14 A-2 Quant. II-16

II-15 A-6 Quant.

Starting Yield No. R1 R2 Material Method % III- 03

III-02 A-2 71 III- 04

III-03 A-6 Quant. III- 05

III-01 A-1 29 III- 06

III-05 A-2 72 III- 07

III-06 A-6 Quant. III- 08

Br III-01 A-1 98 III- 09

III-08 A-1 25 III- 10

III-09 A-2 40 III- 11

III-10 A-6 Quant. III- 12

III-08 A-1 50 III- 13

III-12 A-2 46 III- 14

III-13 A-6 Quant. III- 15

III-05 A-2 48 III- 16

III-15 A-8 50 III- 17

III-16 A-6 Quant. III- 18

III-06 A-5 Quant.

Starting Yield No. R1 R2 Material Method % IV- 03

IV-02 A-3 67 IV- 04

IV-03 A-2 57 IV- 05

IV-04 A-6 Quant. IV- 06 Cl

IV-01 A-1 90 IV- 07

IV-06 A-3 83 IV- 08

IV-07 A-2 75 IV- 09

IV-08 A-6 Quant. IV- 10 Cl

IV-01 A-1 62 IV- 11

IV-10 A-3 94 IV- 12

IV-11 A-2 65 IV- 13

IV-12 A-6 Quant. IV- 14 Cl

IV-01 A-1 90 IV- 15

IV-14 A-1 72 IV- 16

IV-15 A-2 84 IV- 17

IV-16 A-6 Quant.

Starting Yield No. R1 R2 Material Method % V-03 Br

V-02 A-1 60 V-04

V-03 A-1 62 V-05

V-04 A-6 Quant.

Starting Yield No. R1 R2 Material Method % VI-02

Cl

VI-01 Commercially Available A-1 20 VI-03

VI-02 A-1 89 VI-04

VI-03 A-6 Quant. VI-05

Cl VI-01 A-1 67 VI-06

VI-05 A-1 78 VI-07

VI-06 A-2 49 VI-08

VI-07 A-6 Quant.

Starting Yield No. R1 R2 Material Method % VII- 02 Br

VII-01 Commerically A-1 68 Available VII- 03

VII-02 A-1 95 VII- 04

VII-03 A-2 62 VII- 05

VII-04 A-6 Quant. VII- 06 Br

VII-01 A-4 Quant. VII- 07

VII-06 A-3 84 VII- 08

VII-07 A-2 37 VII- 09

VII-08 A-6 Quant. VII- 10 Br

VII-01 A-3 15 VII- 11

VII-10 A-3 61 VII- 12

VII-11 A-2 43 VII- 13

VII-12 A-6 Quant. VII- 14 Br

VII-01 A-3  4 VII- 15

VII-14 A-3 95 VII- 16

VII-15 A-2 31 VII- 17

VII-16 A-6 Quant.

Starting Yield No. R1 R2 Material Method % VIII-  02

Cl

VIII-01  Commercially A-1  79 Available VIII-  03

VIII-02  A-3  63 VIII-  04

VIII-03  A-2  37 VIII-  05

VIII-04  A-6 Quant. VIII-  06

VIII-02  A-1  64 VIII-  07

VIII-06  A-2  62 VIII-  08

VIII-07  A-6 Quant. VIII-  09

VIII-02  A-3  53 VIII-  10

VIII-09  A-2  61 VIII-  11

VIII-10  A-6 Quant. VIII-  12

VIII-02  A-4  83 VIII-  13

VIII-12  A-2  63 VIII-  14

VIII-13  A-6 Quant. VIII-  15

VIII-02  A-3  54 VIII-  16

VIII-15  A-2  42 VIII-  17

VIII-16  A-6 Quant. VIII-  18

VIII-01  A-1  39 VIII-  19

VIII-18  A-2  26 VIII-  20

VIII-19  A-6 Quant. VIII-  21

VIII-03  A-2  54 VIII-  22

VIII-21  A-8  83 VIII-  23

VIII-22  A-6 Quant. VIII-  24

VIII-04  A-5 Quant. VIII-  25

Cl VIII-02  A-2  28 VIII-  26

VIII-25  A-3  43 VIII-  27

VIII-03  A-2  70 VIII-  28

VIII-27  A-6 Quant. VIII-  29

Cl VIII-01  A-3  98 VIII-  30

VIII-29  A-3  57 VIII-  31

VIII-30  A-2  62 VIII-  32

VIII-31  A-6 Quant. VIII-  33

VIII-03  A-2  44 VIII-  34

VIII-33  A-6 Quant. VIII-  35

VIII-03  A-2  37 VIII-  36

VIII-35  A-6 Quant. VIII-  37

VIII-02  A-1  61 VIII-  38

VIII-37  A-2  64 VIII-  39

VIII-38  A-6 Quant. VIII-  40

Cl VIII-01  A-1  63 VIII-  41

VIII-40  A-1  74 VIII-  42

VIII-41  A-6 Quant. VIII-  43

VIII-29  A-1  56 VIII-  44

VIII-43  A-2  34 VIII-  45

VIII-44  A-6 Quant. VIII-  46

VIII-02  A-4  75 VIII-  47

VIII-46  A-2  71 VIII-  48

VIII-47  A-6 Quant. VIII-  49

VIII-02  A-1  45 VIII-  50

VIII-49  A-2  40 VIII-  51

VIII-50  A-6 Quant. VIII-  52

VIII-02  A-4  75 VIII-  53

VIII-52  A-2  65 VIII-  54

VIII-53  A-6 Quant. VIII-  55

VIII-02  A-1  80 VIII-  56

VIII-55  A-2  57 VIII-  57

VIII-56  A-6 Quant. VIII-  58

VIII-02  A-4  93 VIII-  59

VIII-58  A-2  74 VIII-  60

VIII-59  A-6 Quant. VIII-  61

VIII-02  A-1 100 VIII-  62

VIII-61  A-2  18 VIII-  63

VIII-62  A-6 Quant. VIII-  64

Cl VIII-02  A-2  67 VIII-  65

VIII-64  A-1  71 VIII-  66

VIII-65  A-8  92 VIII-  67

VIII-66  A-6 Quant. VIII-  68

VIII-02  A-4  84 VIII-  69

VIII-68  A-2  80 VIII-  70

VIII-69  A-6 Quant. VIII-  71

VIII-02  A-4  91 VIII-  72

VIII-71  A-2  68 VIII-  73

VIII-72  A-6 Quant. VIII-  74

VIII-64  A-1  32 VIII-  75

VIII-74  A-8 Quant. VIII-  76

VIII-75  A-6 Quant. VIII-  77

VIII-64  A-1 Quant. VIII-  78

VIII-77  A-8  16 VIII-  79

VIII-78  A-6 Quant. VIII-  80

VIII-37  A-2  50 VIII-  81

VIII-80  A-6 Quant. VIII-  82

VIII-02  A-4  91 VIII-  83

VIII-82  A-2  78 VIII-  84

VIII-83  A-6 Quant. VIII-  85

VIII-02  A-4  93 VIII-  86

VIII-85  A-2  77 VIII-  87

VIII-86  A-6 Quant. VIII-  88

VIII-02  A-4  80 VIII-  89

VIII-88  A-2  85 VIII-  90

VIII-89  A-6 Quant. VIII-  91

VIII-02  A-4  86 VIII-  92

VIII-91  A-2  90 VIII-  93

VIII-92  A-6 Quant. VIII-  94

VIII-64  A-1 Quant. VIII-  95

VIII-94  A-8  95 VIII-  96

VIII-02  A-1  17 VIII-  97

VIII-96  A-2  74 VIII-  98

VIII-97  A-6  25 VIII-  99

VIII-02  A-1  77 VIII- 100

VIII-99  A-2  75 VIII- 101

VIII-100 A-6 Quant. VIII- 102

VIII-99 A-2  56 VIII- 103

VIII-102 A-6 Quant. VIII- 104

VIII-99  A-2  60 VIII- 105

VIII-104 A-6 Quant.

Starting Yield No. R1 R2 Material Method % IX- 02

Br

IX-01 Commercially Available A-3 57 IX- 03

IX-02 A-3 72 IX- 04

IX-03 A-2 71 IX- 05

IX-04 A-6 Quant. IX- 06

IX-02 A-3 69 IX- 07

IX-06 A-2 58 IX- 08

IX-07 A-6 Quant. IX- 09

IX-02 A-1 66 IX- 10

IX-09 A-2 41 IX- 11

IX-10 A-6 Quant.

Starting Yield No. R1 R2 Material Method % X- 02

Cl

X-01 Commercially A-1 80 Available X- 03

Cl X-02 A-2 24 X- 04

X-03 A-1 51 X- 05

X-04 A-6 Quant. X- 06

X-03 A-1 70 X- 07

X-06 A-6 Quant. X- 08

X-02 A-1 18 X- 09

X-08 A-2 31 X- 10

X-09 A-8 48 X- 11

X-10 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XI-02

Cl

XI-01 Commercially A-1 92 Available XI-03

XI-02 A-1 Quant. XI-04

XI-03 A-2 96 XI-05

XI-04 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XII- H Cl 1-05 A-10  72 01XII- I Cl XII-01 A-11  71 02 XII- 03

Cl XII-02 A-1  83 XII- 04

XII-03 A-1 100 XII- 05

XII-04 A-2  41 XII- 06

XII-05 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XIII- H Cl 1-07 A-10 20 01XIII- I Cl XIII-01 A-11 77 02 XIII- 03

Cl XIII-02 A-1 70 XIII- 04

XIII-03 A-1 50 XIII- 05

XIII-04 A-2 66 XIII- 06

XIII-05 A-6 Quant. XIII- 07

XIII-03 A-1 64 XIII- 08

XIII-07 A-2 56 XIII- 09

XIII-08 A-6 Quant. XIII- 10

XIII-03 A-1 64 XIII- 11

XIII-10 A-2 76 XIII- 12

XIII-11 A-6 Quant. XIII- 13

XIII-10 A-2 19 XIII- 14

XIII-13 A-6 Quant. XIII- 15

Cl XIII-03 A-2 50 XIII- 16

XIII-15 A-1 Quant. XIII- 17

XIII-16 A-8 95 XIII- 18

XIII-03 A-4 85 XIII- 19

XIII-18 A-2 93 XIII- 20

XIII-19 A-8 Quant. XIII- 21

XIII-20 A-6 Quant. XIII- 22

XIII-03 A-1 Quant. XIII- 23

XIII-22 A-2 95% XIII- 24

XIII-23 A-8 97% XIII- 25

XIII-24 A-6 Quant. XIII- 26

XIII-03 A-4 98 XIII- 27

XIII-26 A-2 80 XIII- 28

XIII-27 A-8 86 XIII- 29

XIII-28 A-6 Quant. XIII- 30

XIII-03 A-1 98 XIII- 31

XIII-30 A-2 66 XIII- 32

XIII-31 A-6 Quant. XIII- 33

XIII-03 A-4 98 XIII- 34

XIII-33 A-2 82 XIII- 35

XIII-34 A-8 Quant. XIII- 36

XIII-35 A-6 Quant. XIII- 37

XIII-10 A-2 56 XIII- 38

XIII-37 A-6 Quant. XIII- 39

XIII-10 A-2 80 XIII- 40

XIII-39 A-8 95 XIII- 41

XIII-40 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XIV- H Cl 1-08 A-10 91 01XIV- I Cl XIV-01 A-11 90 02 XIV- 03

Cl XIV-02 A-1 74 XIV- 04

XIV-03 A-1 99 XIV- 05

XIV-04 A-2 40 XIV- 06

XIV-05 A-6 Quant. XIV- 07

XIV-03 A-1 81 XIV- 08

XIV-07 A-2 30 XIV- 09

XIV-08 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XV- 02 H Cl

A-10 78 XV-01 Commercially Available XV- I Cl XV-02 A-11 88 03 XV- 04

Cl XV-03 A-1 79 XV- 05

XV-04 A-1 85 XV- 06

XV-05 A-2 44 XV- 07

XV-06 A-6 Quant. XV- 08

XV-05 A-2 32 XV- 09

XV-08 A-6 Quant. XV- 10

XV-04 A-1 43 XV- 11

XV-10 A-2 82 XV- 12

XV-11 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XVI- 02 I Cl

A-11 23 XVI-01 Commercially Available XVI- 03

XVI-02 A-1 96 XVI- 04

XVI-03 A-2 57 XVI- 05

XVI-04 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XVII- 02

Cl

XVII-01 Commercially Available A-1 44 XVII- 03

XVII-02 A-3 61 XVII- 04

XVII-03 A-6 Quant. XVII- 05

XVII-02 A-3 35 XVII- 06

XVII-05 A-6 Quant.

Starting Yield No. R1 R2 Material Method % XVIII- 02 I Cl

A-11 86 XVIII-01 Commercially Available XVIII- 03

Cl XVIII-02 A-1 84 XVIII- 04

XVIII-03 A-3 Quant. XVIII- 05

XVIII-04 A-2 48 XVIII- 06

XVIII-05 A-8 82 XVIII- 07

XVIII-06 A-6 Quant.

The final examples of compounds of the invention were prepared accordingto the general methods B-1 to B-4 described hereinafter.

EXAMPLES

General Method B-1

The corresponding aminoacid intermediate (1 eq.) was dissolved in DMF(50 mL/mmol) and DI PEA (5 eq.) was added. The mixture was added using asyringe pump (2 mL/h) to a solution of PyBOP (1.1 eq.) and DMAP (1.1eq.) in DMF (150 mL/mmol). After the addition, the mixture was stirredfor 18 h and evaporated till dryness. The residue was purified by flashchromatography in a Biotage using cyclohexane/AcOEt gradient followed byAcOEt/MeOH gradient to give the expected compound.

General Method B-2

A solution of the indicated aminoacid intermediate (1 eq.) in DMF (50mL/mmol) and DIPEA (5 eq.) was added via syringe pump (2 mL/h) to asolution of HATU (2 eq.) and HOAt (0.5 M in DMF, 2 eq.) in DMF (150mL/mmol). The resulting mixture was stirred overnight under Ar. Themixture was concentrated under vacuum. The residue was purified by flashchromatography in a Biotage using DCM/MeOH gradient to give the expectedcompound.

General Method B-3

A solution of the indicated aminoacid intermediate (1 eq.) in DMF (50mL/mmol) and DIPEA (5 eq.) was added via syringe pump (2 mL/h) to asolution of PyBroP (2 eq.) in DMF (150 mL/mmol). The resulting mixturewas stirred overnight under Ar. The mixture was concentrated undervacuum. The residue was purified by flash chromatography in a Biotageusing DCM/MeOH gradient to give the expected compound.

Method B-4

Synthesis of Final Product 46

To a solution of Final Product 27 (30 mg, 0.06 mmol) in DMF (0.6 mL) andDIPEA (10 μL 0.06 mmol) was added MeI (4 μL, 0.06 mmol) at 0° C. Themixture was stirred from 0° C. to rt. More DIPEA (10 μL) and MeI (5 μL)were added and the reaction was stirred at rt for 6 h. Water was addedand the mixture was extracted with DCM. The organic layer was dried(Na₂SO₄), filtered and concentrated. The residue was purified by prepHPLC to give Final Product 46 (4 mg, 13%) and the dimethylated product(3 mg, 9%).

TABLE 2 Final products Cpd. Starting General Yield Nr. StructureMaterial Method %  1

I-07 B-1 12  2

I-08 B-1 23  3

I-13 B-1 31  4

I-17 B-1 57  5

I-11 B-1 20  6

I-14 B-1 38  7

I-15 B-1 73  8

II-04 B-2 19  9

II-05 B-2 21  10

I-16 B-1 26  11

III-04 B-2 40  12

IV-05 B-2 53  13

IV-09 B-2 43  14

II-10 B-2 1  15

I-19 B-1 14  16

III-07 B-2 18  17

II-13 B-2 43  18

IV-13 B-2 12  19

I-21 B-1 5  20

V-05 B-1 5  21

VI-04 B-2 3  22

VII-05 B-2 36  23

IV-17 B-2 4  24

I-23 B-3 6  25

III-11 B-2 4  26

III-14 B-2 30  27

VIII-05 B-2 31  28

VIII-08 B-2 19  29

I-25 B-1 47  30

IX-05 B-2 15  31

X-05 B-2 18  32

VII-09 B-2 53  33

VII-13 B-2 51  34

IX-08 B-2 38  35

X-07 B-2 32  36

VIII-11 B-2 18  37

VI-08 B-2 8  38

VIII-14 B-2 6  39

I-28 B-2 34  40

IX-11 B-2 21  41

VII-17 B-2 29  42

VIII-17 B-2 30  43

VIII-20 B-2 10  44

VIII-23 B-2 19  45

VIII-24 B-2 10  46

27 B-4 13  47

VIII-26 B-2 14  48

VIII-28 B-2 38  49

I-32 B-1 11  50

VIII-32 B-2 19  51

XI-05 B-2 7  52

VIII-34 B-2 34  53

VIII-36 B-2 35  54

XII-06 B-2 29  55

VIII-39 B-2 20  56

XIII-06 B-2 36  57

XIII-09 B-2 25  58

VIII-42 B-2 13  59

VIII-45 B-2 19  60

XIV-06 B-2 22  61

XIV-09 B-2 13  62

XV-07 B-2 33  63

XV-09 B-2 42  64

VIII-48 B-2 27  65

VIII-50 B-2 59  66

VIII-54 B-2 29  67

III-17 B-2 29  68

XIII-12 B-2 4  69

VIII-57 B-2 15  70

VIII-60 B-2 20  71

X-11 B-2 9  72

VIII-63 B-2 17  73

XVI-05 B-2 34  74

VIII-67 B-2 16  75

VIII-70 B-2 3  76

VIII-73 B-2 43  77

VIII-76 B-2 9  78

XVII-04 B-2 26  79

VIII-79 B-2 52  80

XV-12 B-2 18  81

XVII-06 B-2 19  82

VIII-81 B-2 33  83

VIII-84 B-2 25  84

VIII-87 B-2 32  85

III-18 B-2 3  86

VIII-90 B-2 20  87

VIII-93 B-2 27  88

VIII-95 B-2 4  89

VIII-98 B-2 25  90

XIII-14 B-2 16  91

XIII-21 B-2 49  92

XIII-25 B-2 37  93

VIII-101 B-2 24  94

XIII-29 B-2 42  95

XIII-32 B-2 29  96

II-16 B-2 1  97

VIII-103 B-2 17  98

VIII-105 B-2 16  99

XIII-36 B-2 29 100

XIII-38 B-2 25 101

XVIII-07 B-2 31 102

XIII-41 B-2 26

Certain exemplary compounds of the invention described herein wereprepared, characterised and assayed for their PI3Kα, PIM-1 and mTORenzymatic activities.

TABLE 3 Analytical data and PI3K alpha, PIM-1 and mTOR activities Cpd.¹H NMR (300 MHz; δ in Nr. R_(t) [M + 1]⁺ Meth. PI3K mTOR PIM1 ppm, J inHz) 1 3.67 524.3 1 *** *** * DMSO-d₆ δ 9.86 (s, 1H), (2) (64) 9.40 (t, J= 5.7 Hz, 1H), 9.01 (d, J = 4.4 Hz, 1H), 8.73 (m, 2H), 8.21 (d, J = 8.7Hz, 1H), 8.14 (m, 1H), 8.06 (m, 3H), 7.98 (m, 2H), 7.71 (m, 3H), 7.60(d, J = 4.4 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.76 (s, 3H). 2 3.11510.0 1 ** * * DMSO-d₆ δ 11.96 (very broad s, 1H), 9.41 (t, J = 5.6 Hz,1H), 8.99 (d, J = 4.4 Hz, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.72 (d, J =1.9 Hz, 1H), 8.17 (m, 3H), 8.06 (m, 2H), 7.89 (dd, J = 8.7, 1.8 Hz, 1H),7.70 (t, J = 7.8 Hz, 1H), 7.58 (m, 3H), 7.21 (d, J = 2.1 Hz, 1H), 4.54(d, J = 5.5 Hz, 2H). 3 4.21 523.1 1 *** ** * DMSO-d₆ δ 9.84 (broad s,(1.6) 1H), 9.37 (t, J = 5.9 Hz, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.18 (d,J = 8.7 Hz, 1H), 8.03 (m, 3H), 7.91 (m, 2H), 7.70 (m, 2H), 7.62 (m, 2H),7.58 (d, J = 7.3 Hz, 1H), 7.51 (m, 3H), 4.50 (d, J = 5.7 Hz, 2H), 3.73(s, 3H). 4 4.69 541.1 1 *** ** * DMSO-d₆ δ 9.86 (s, 1H), (3) 9.31 (t, J= 5.8 Hz, 1H), 9.00 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.20(m, 4H), 7.70 (t, J = 7.9 Hz, 1H), 7.58 (m, 5H), 7.43 (dd, J = 9.7, 8.5Hz, 1H), 4.46 (m, 2H), 3.73 (s, 3H). 5 4.55 541.1 1 *** ** * DMSO-d₆ δ9.83 (s, 1H), (23) 9.35 (m, 1H), 9.02 (d, J = 4.3 Hz, 1H), 8.19 (d, J =8.7 Hz, 1H), 8.13 (m, 1H), 8.03 (m, 3H), 7.97 (dd, J = 8.7, 1.9 Hz, 1H),7.70 (m, 3H), 7.51 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 4.69 (dd, J =13.7, 6.5 Hz, 1H), 4.36 (dd, J = 13.9, 3.3 Hz, 1H), 3.80 (s, 3H). 6 2.90530.2 1 *** *** * DMSO-d₆ δ 10.16 (broad s, (11) (72) 1H), 8.93 (t, J =6.2 Hz, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.31 (m, 1H), 8.24 (m, 2H), 8.01(m, 2H), 7.95 (d, J = 2.2 Hz, 1H), 7.91 (m, 2H), 7.79 (t, J = 7.8 Hz,1H), 7.05 (d, J = 4.9 Hz, 1H), 3.94 (s, 3H), 3.50 (m, 2H), 3.37 (m, 2H),2.77 (m, 2H), 1.81 (m, 3H), 1.65 (m, 2H). 7 3.07 504.1 1 * * * DMSO-d₆ δ8.92 (m, 1H), 8.82 (t, J = 5.5 Hz, 1H), 8.62 (m, 2H), 8.53 (d, J = 7.1Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.24 (dd, J = 8.8, 1.4 Hz, 1H), 8.17(m, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.01 (s, 3H), 3.60 (m, 2H),3.37 (m, 2H), 1.83 (m, 2H), 1.62 (m, 2H). 8 3.87 520.2 1 *** * * DMSO-d₆δ 10.56 (s, 1H), (7) 9.70 (t, J = 5.8 Hz, 1H), 8.95 (s, 1H), 8.79 (s,1H), 8.57 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.21 (m, 2H), 8.16 (d, J =7.8 Hz, 1H), 7.97 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.80 (t, J = 7.8Hz, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H). 9 3.14 506.0 1 ** * **DMSO-d₆ δ 9.60 (t, J = 5.5 Hz, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.64 (s,1H), 8.55 (d, J = 1.9 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.12 (m, 1H),8.04 (m, 1H), 7.90 (s, 1H), 7.72 (m, 1H), 7.59 (m, 1H), 7.35 (m, 1H),4.66 (d, J = 5.5 Hz, 2H). 10 3.94 560.1 1 *** *** * DMSO-d₆ δ 10.47 (s,1H), (0.03) (22) 9.14 (t, J = 5.4 Hz, 1H), 9.02 (d, J = 4.4 Hz, 1H),8.74 (m, 2H), 8.22 (d, J = 8.7 Hz, 1H), 7.99 (m, 3H), 7.72 (m, 3H), 7.60(d, J = 4.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 4.52 (d, J = 5.5 Hz, 2H),3.77 (s, 3H). 11 3.27 514.1 1 *** *** * DMSO-d₆ δ 9.97 (s, 1H), (0.4)(4) 9.68 (t, J = 5.8 Hz, 1H), 9.23 (d, J = 7.4 Hz, 1H), 8.94 (d, J = 1.3Hz, 1H), 8.81 (s, 1H), 8.74 (m, 2H), 8.49 (d, J = 1.3 Hz, 1H), 8.34 (t,J = 1.8 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.09 (m, 1H), 8.03 (m, 1H),7.70 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 4.60 (d, J = 5.6 Hz,2H), 4.02 (s, 3H). 12 3.32 514.1 1 *** *** * DMSO-d₆ δ 9.93 (broad s,(0.4) (5) 1H), 9.56 (t, J = 5.6 Hz, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.60(d, J = 1.6 Hz, 1H), 8.48 (m, 1H), 8.37 (m, 3H), 8.04 (m, 2H), 7.92 (d,J = 2.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 9.5 Hz, 1H),4.56 (d, J = 5.5 Hz, 2H), 3.91 (s, 3H). 13 4.09 513.1 1 *** *** *DMSO-d₆ δ 9.91 (broad s, (0.4) (10) 1H), 9.46 (t, J = 5.7 Hz, 1H), 8.37(m, 2H), 8.27 (d, J = 9.4 Hz, 1H), 8.14 (s, 1H), 8.03 (m, 3H), 7.88 (d,J = 2.2 Hz, 1H), 7.69 (m, 2H), 7.61 (d, J = 9.5 Hz, 1H), 7.50 (t, J =7.6 Hz, 1H), 7.40 (m, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H). 143.37 577.1 1 ** * ** DMSO-d₆ δ 10.04 (broad s, 1H), 8.96 (t, J = 5.9 Hz,1H), 8.92 (d, J = 2.0 Hz, 1H), 8.57 (t, J = 5.8 Hz, 1H), 8.50 (m, 2H),8.44 (m, 1H), 8.16 (d, J = 2.2 Hz, 1H), 8.10 (m, 3H), 7.94 (s, 1H), 7.75(m, 1H), 4.36 (d, J = 5.9 Hz, 2H), 3.84 (d, J = 5.8 Hz, 2H), 3.77 (s,3H). 15 3.89 524.1 1 *** ** * DMSO-d₆ δ 9.87 (broad s, (20) 1H), 9.49(t, J = 5.8 Hz, 1H), 9.02 (d, J = 4.4 Hz, 1H), 8.75 (d, J = 5.1 Hz, 1H),8.19 (d, J = 8.7 Hz, 1H), 8.15 (m, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.00(m, 2H), 7.91 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (m, 2H), 7.65 (s, 1H),7.57 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H), 3.79(s, 3H). 16 4.87 513.1 1 *** *** * DMSO-d₆ δ 9.90 (s, 1H), (0.9) (4)9.57 (t, J = 5.7 Hz, 1H), 9.18 (d, J = 7.4 Hz, 1H), 8.72 (m, 2H), 8.62(s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.99 (m,2H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H),7.43 (t, J = 7.6 Hz, 1H), 7.27 (m, 1H), 4.58 (d, J = 5.7 Hz, 2H), 4.01(s, 3H). 17 4.97 519.0 1 *** ** * DMSO-d₆ δ 10.52 (s, 1H), (9) 9.67 (t,J = 5.8 Hz, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 8.16 (t, J = 8.0 Hz, 2H),7.94 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.82- 7.73 (m, 2H), 7.68 (d, J =7.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 4.64(d, J = 5.7 Hz, 2H), 4.01 (s, 3H). 18 3.29 517.2 1 *** *** * DMSO-d₆ δ10.36 (s, 1H), (5) (67) 8.75 (t, J = 5.4 Hz, 1H), 8.62 (d, J = 1.9 Hz,1H), 8.51 (m, 1H), 8.23 (d, J = 4.7 Hz, 2H), 8.18 (d, J = 9.5 Hz, 1H),8.02 (m, 2H), 7.85 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.76(d, J = 9.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 4.48 (s, 2H), 4.04 (s,3H), 3.72 (s, 2H). 19 3.24 527.1 1 *** *** * DMSO-d₆ δ 10.28 (bs, 1H),(4) (21) 8.86 (d, J = 4.5 Hz, 2H), 8.34 (s, 1H), 8.30 (s, 1H), 8.21 (s,1H), 8.13-8.05 (m, 3H), 8.05-7.94 (m, 2H), 7.90 (s, 1H), 7.75-7.62 (m,2H), 7.50 (d, J = 4.5 Hz, 1H), 4.43 (s, 2H), 3.95 (s, 3H), 3.78 (s, 2H).20 3.18 513.0 1 *** ** * DMSO-d₆ δ 12.26 (s, 1H), (80) 10.12 (s, 1H),9.62 (t, J = 5.6 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.81 (s, 1H), 8.50(d, J = 2.0 Hz, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.22-8.11 (m, 4H), 8.07(d, J = 1.8 Hz, 1H), 7.81- 7.74 (m, 1H), 7.74 (d, J = 2.2 Hz, 1H), 4.61(d, J = 5.5 Hz, 2H), 3.94 (s, 3H). 21 4.44 531.1 1 *** * ** DMSO-d₆ δ9.56 (t, J = 5.3 (85) Hz, 1H), 9.16 (s, 1H), 9.09 (s, 1H), 9.02 (s, 1H),8.80 (s, 1H), 8.44 (s, 1H), 8.13 (m, 3H), 7.74 (m, 3H), 4.68 (d, J = 5.2Hz, 2H), 3.94 (s, 3H). 22 4.67 524.1 1 *** *** * DMSO δ 9.87 (s, 1H),9.42 (t, (0.1) (30) J = 5.5 Hz, 1H), 9.38 (s, 1H), 8.18 (s, 2H), 8.14(s, 1H), 8.04 (m, 3H), 7.93 (s, 1H), 7.72 (m, 2H), 7.80 (m, 2H), 7.63(m, 2H), 4.53 (d, J = 5.5 Hz, 2H), 3.76 (s, 3H). 23 0.41 532.2 1 ****** * DMSO δ 8.59 (t, J = 5.5 Hz, (5) (22) 1H), 8.52 (d, J = 1.8 Hz,1H), 8.16 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 8.04 (m, 1H), 7.96 (d, J =2.0 Hz, 1H), 7.92 (m, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.75 (s, 1H), 7.65(t, J = 7.8 Hz, 1H), 6.42 (m, 1H), 4.02 (s, 3H), 3.49 (m, 2H), 3.36 (m,2H), 2.82 (t, J = 5.2 Hz, 2H), 2.76 (m, 2H), 2.61 (s, 2H). 24 2.88 544.21 *** *** * DMSO δ 8.62 (d, J = 4.8 Hz, (3) (4) 1H), 8.15 (s, 1H), 8.02(m, 2H), 7.96 (m, 2H), 7.67 (m, 4H), 6.91 (d, J = 4.9 Hz, 1H), 4.02 (s,3H), 3.40 (m, 4H), 3.05 (s, 3H), 2.73 (m, 2H), 1.94 (m, 1H), 1.71 (m,2H), 0.95 (m, 2H). 25 2.71 522.3 1 *** *** * DMSO δ 8.87 (d, J = 7.5 Hz,(20) (54) 1H), 8.68 (t, J = 5.3 Hz, 1H), 8.51 (s, 1H), 8.22 (s, 1H),8.18 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (m, 2H), 7.56 (m, 2H), 6.20(m, 1H), 3.9 (s, 3H), 3.48 (m, 2H), 3.34 (m, 2H), 2.90 (m, 2H), 2.77 (m,2H), 2.60 (m, 2H). 26 3.99 517.3 1 *** *** * DMSO δ 10.14 (s, 1H), 9.07(4) (40) (d, J = 7.5 Hz, 1H), 8.84 (t, J = 5.2 Hz, 1H), 8.80 (d, J = 1.7Hz, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.96 (m, 1H), 7.86(m, 1H), 7.81 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.56 (m, 2H), 4.45 (m,2H), 4.04 (s, 3H), 3.66 (s, 2H). 27 4.18 531.1 1 ** * *** DMSO δ 10.74(s, 1H), 9.90 (40) (t, J = 6.0 Hz, 1H), 9.29 (s, 1H), 9.26 (d, J = 1.9Hz, 1H), 8.88 (m, 2H), 8.67 (s, 1H), 8.49 (m, 1H), 8.28 (d, J = 7.7 Hz,1H), 8.21 (m, 2H), 7.83 (m, 1H), 7.44 (s, 1H), 4.73 (d, J = 5.8 Hz, 2H),4.03 (s, 3H). 28 4.92 530.2 1 ** * ** DMSO δ 10.71 (s, 1H), 9.90 (t, J =5.7 Hz, 1H), 9.24 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.27 (d, J = 7.5Hz, 1H), 8.19 (m, 4H), 7.81 (m, 1H), 7.65 (d, J = 4.5 Hz, 2H), 7.46 (d,J = 1.8 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 4.02 (s, 3H). 29 4.51 559.3 1*** ** * DMSO δ 10.46 (s, 1H), 9.13 (6) (t, J = 5.7 Hz, 1H), 8.98 (d, J= 4.4 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.97 (dd, J = 8.7, 1.9 Hz, 1H),7.94 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.58 (m, 8H), 4.46(m, 2H), 3.76 (s, 3H). 30 2.58 513.1 1 *** *** * DMSO δ 9.40 (t, J = 5.2Hz, (11) (49) 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.69 (s, 1H), 8.61 (m, 2H),8.44 (t, J = 1.9 Hz, 1H), 8.22- 8.04 (m, 3H), 7.96 (s, 1H), 7.91 (d, J =2.2 Hz, 1H), 7.82- 7.66 (m, 2H), 7.59 (dd, J = 9.4, 1.5 Hz, 1H), 4.59(d, J = 5.2 Hz, 2H), 3.93 (s, 3H). 31 3.57 525.1 1 *** *** * DMSO δ 9.83(s, 1H), 9.26 (t, (2) (23) J = 6.1 Hz, 1H), 9.09 (d, J = 4.4 Hz, 1H),8.83 (m, 1H), 8.67 (m, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.32-8.17 (m, 2H),8.08-7.93 (m, 4H), 7.91 (d, J = 4.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H),7.59 (m, 1H), 4.50 (d, J = 5.9 Hz, 2H), 3.50 (s, 3H). 32 2.83 531.2 1*** *** * DMSO δ 10.09 (s, 1H), 8.85 (2) (5) (t, J = 6.1 Hz, 1H), 8.62(s, 1H), 8.37-8.26 (m, 2H), 8.16 (m, 1H), 8.05 (m, 2H), 7.85 (d, J = 8.7Hz, 1H), 7.81- 7.65 (m, 3H), 4.05 (m, 2H), 3.98 (s, 3H), 3.59-3.44 (m,2H), 3.04 (t, J = 11.9 Hz, 2H), 2.01 (m, 1H), 1.93- 1.61 (m, 4H). 334.16 528.2 1 *** *** * DMSO δ 10.23 (s, 1H), 9.19 (1.3) (4.8) (s, 1H),8.98 (t, J = 5.8 Hz, 1H), 8.69 (s, 1H), 8.42 (t, J = 1.9 Hz, 1H),8.30-8.00 (m, 7H), 7.72 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H),4.42 (m, 2H), 3.97 (s, 3H), 3.77 (m, 2H). 34 3.14 516.1 1 *** *** * DMSOδ 10.15 (s, 1H), 9.02 (7.6) (66) (t, J = 5.7 Hz, 1H), 8.49 (m, 1H), 8.36(s, 1H), 8.21 (s, 1H), 8.19-8.08 (m, 3H), 7.85 (s, 1H), 7.78-7.62 (m,3H), 7.56 (d, J = 2.2 Hz, 1H), 7.47 (dd, J = 9.2, 1.8 Hz, 1H), 4.39 (m,2H), 3.96 (s, 3H), 3.81-3.60 (m, 2H). 35 4.69 524.3 1 *** *** * DMSO δ9.81 (s, 1H), 9.20 (t, (5) (16) J = 6.0 Hz, 1H), 9.04 (d, J = 4.4 Hz,1H), 8.56 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.07 (d, J =2.3 Hz, 1H), 8.02-7.93 (m, 3H), 7.81 (m, 1H), 7.76 (d, J = 4.4 Hz, 1H),7.74-7.58 (m, 3H), 7.53 (t, J = 7.5 Hz, 1H), 7.44(m, 1H), 4.45 (d, J =6.0 Hz, 2H), 3.52 (s, 3H). 36 4.11 534.2 1 ** * ** DMSO δ 10.76 (s, 1H),9.20 (t, J = 5.4 Hz, 1H), 9.06 (s, 1H), 8.90 (m, 1H), 8.65 (d, J = 2.3Hz, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.14 (m, 2H), 8.09 (s, 1H), 7.73(t, J = 7.8 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 4.61 (m, 2H), 4.03 (s,3H), 3.70 (m, 2H). 37 5.23 530.0 1 *** * * DMSO δ 10.34 (s, 1H), 9.63(20) (t, J = 4.8 Hz, 1H), 9.14 (s, 1H), 9.11 (s, 1H), 8.21 (m, 3H), 8.05(s, 1H), 7.97 (m, 1H), 7.88 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.79 (t,J = 7.8 Hz, 1H), 7.63 (m, 2H), 4.65 (d, J = 4.9 Hz, 2H), 3.99 (s, 3H).38 3.15 537.2 1 * * * DMSO δ 10.49 (s, 1H), 8.64 (m, 1H), 8.53 (m, 2H),8.41 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.62(m, 2H), 6.85 (s, 1H), 4.38 (m, 2H), 4.01 (s, 3H), 3.50 (m, 2H), 3.23(m, 2H), 2.14 (m, 1H), 1.67 (m, 2H), 1.25 (d, J = 7.0 Hz, 2H). 39 4.47549.3 1 *** *** * DMSO δ 10.18 (s, 1H), 8.91 (0.05) (0.3) (d, J = 4.4Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.16 (m, 2H), 7.96 (m, 1H), 7.91 (s,1H), 7.75 (m, 3H), 7.66 (d, J = 2.2 Hz, 1H), 7.47 (m, 3H), 7.43 (s, 1H),4.54 (s, 2H), 4.02 (s, 3H), 3.93 (m, 2H), 3.08 (m, 2H). 40 1.19 531.3 1*** *** * DMSO δ 10.55 (broad s, 1H), (3) (36) 8.62 (t, J = 5.5 Hz, 1H),8.40 (m, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.06 (m, 2H), 8.00 (s, 1H), 7.70(t, J = 7.8 Hz, 1H), 7.63 (d, J = 9.4 Hz, 1H), 7.53 (m, 3H), 6.04 (m,1H), 3.97 (s, 3H), 3.53 (m, 2H), 3.25 (m, 2H), 2.76 (m, 4H), 2.39 (m,2H). 41 3.96 525.0 1 *** *** * DMSO δ 9.88 (broad s, 1H), (3) (16) 9.44(m, 2H), 8.95 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.5 Hz, 1H), 8.25 (m,4H), 8.08 (m, 3H), 7.99 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.73 (t, J =7.8 Hz, 1H), 4.59 (d, J = 5.3 Hz, 2H), 3.82 (s, 3H). 42 4.42 531.0 1** * ** DMSO δ 10.76 (s, 1H), 9.97 (s, 1H), 9.33 (s, 1H), 8.92 (s, 1H),8.84 (d, J = 5.2 Hz, 1H), 8.66 (s, 1H), 8.32-8.17 (m, 3H), 8.13 (m, 2H),7.83 (t, J = 7.7 Hz, 1H), 7.43 (s, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.02(s, 3H). 43 3.75 501.1 1 *** * *** DMSO δ 9.86 (m, 1H), 9.32 (44) (41)(s, 1H), 9.26 (s, 1H), 8.93- 8.79 (m, 3H), 8.51 (s, 1H), 8.30 (s, 2H),8.22 (m, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.48(m, 1H), 4.73 (d, J = 5.5 Hz, 2H). DMSO δ 11.24 (s, 1H), 9.38 (m, 1H),9.30 (s, 1H), 9.21 (d, J = 1.9 Hz, 1H), 8.83 (s, 1H), 8.68 (m, 1H), 8.61(t, J = 44 4.26 567.0 1 ** * * 7.9 Hz, 1H), 8.40 (m, 1H), 8.23 (s, 1H),7.85 (t, J = 10.3 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 4.73 (d, J = 5.3Hz, 2H), 4.01 (s, 3H). 45 3.38 517.1 1 * * ** DMSO δ 9.87 (s, 1H), 9.25(d, J = 2.0 Hz, 1H), 9.24 (s, 1H), 8.84 (s, 2H), 8.46 (s, 1H), 8.21 (t,J = 7.5 Hz, 2H), 8.03 (s, 1H), 8.01 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H),7.07 (s, 1H), 4.72 (d, J = 5.5 Hz, 2H). 46 4.46 545.0 1 * * * DMSO δ9.74 (t, J = 5.5 Hz, 1H), 9.30 (m, 2H), 8.97 (d, J = 2.1 Hz, 1H), 8.83(m, 1H), 8.67 (m, 1H), 8.50 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.26 (m,1H), 8.23 (s, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H),4.73 (d, J = 5.4 Hz, 2H), 4.07 (s, 3H), 3.19 (s, 3H). 47 4.09 517.0 1*** *** * DMSO δ 10.86 (broad s, 1H), (99) (8.5) 10.62 (s, 1H), 9.24 (s,1H), 8.96 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.56 (d, J =2.3 Hz, 1H), 8.48 (m, 1H), 8.31 (t, J = 2.2 Hz, 1H), 8.03 (s, 1H), 7.85(m, 1H), 7.60 (m, 2H), 7.21 (d, J = 2.3 Hz, 1H), 4.04 (s, 3H). 48 4.29549.1 1 *** * *** DMSO δ 10.74 (s, 1H), 9.47 (48) (52) (m, 1H), 9.29 (s,1H), 9.22 (d, J = 2.2 Hz, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.66 (d, J =2.2 Hz, 1H), 8.56 (dd, J = 6.4, 2.6 Hz, 1H), 8.44 (t, J = 2.2 Hz, 1H),8.22 (m, 2H), 7.75 (dd, J = 10.2, 8.8 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H),4.73 (d, J = 5.7 Hz, 2H), 4.03 (s, 3H). 49 3.39 494.1 1 *** ** * DMSO δ10.32 (s, 1H), 9.35 (68) (t, J = 5.7 Hz, 1H), 9.03 (d, J = 4.4 Hz, 1H),8.79 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.0 Hz,1H), 8.46 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.01 (m, 5H),7.67 (m, 2H), 7.61 (d, J = 4.4 Hz, 1H), 7.52 (t, J = 2.3 Hz, 1H), 4.50(d, J = 5.7 Hz, 2H). 50 4.91 559.2 1 * * * DMSO δ 10.54 (s, 1H), 9.90(m, 1H), 9.27 (m, 2H), 8.88 (d, J = 12.0 Hz, 2H), 8.65 (d, J = 2.0 Hz,1H), 8.49 (s, 1H), 8.25 (m, 3H), 7.84 (t, J = 7.8 Hz, 1H), 7.42 (d, J =2.0 Hz, 1H), 5.37 (m, 1H), 4.74 (d, J = 5.4 Hz, 2H), 1.40 (d, J = 6.2Hz, 6H). 51 3.84 518.2 1 ** * * DMSO δ 10.19 (s, 1H), 9.07 (t, J = 4.7Hz, 1H), 8.89 (s, 1H), 8.83 (m, 2H), 8.32 (s, 1H), 8.28 (s, 1H), 8.01(d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.56 (t, J= 7.8 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H), 4.52 (m, 2H), 4.04 (s, 3H),3.67 (m, 2H). 52 4.24 549.1 1 ** * ** DMSO δ 11.16 (s, 1H), 9.90 (t, J =5.6 Hz, 1H), 9.29 (s, 1H), 9.26 (d, J = 2.1 Hz, 1H), 8.92 (m, 1H), 8.85(s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 8.37 (m, 1H), 8.21 (s, 1H), 7.67(t, J = 9.2 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H),4.01 (s, 1H). 53 4.88 599.1 1 * * * DMSO δ 10.78 (broad s, 1H), 10.12(t, J = 5.6 Hz, 1H), 9.29 (s, 1H), 9.25 (d, J = 1.8 Hz, 1H), 9.18 (s,1H), 8.88 (s, 1H), 8.71 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.51 (s,1H), 8.22 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 4.77 (d, J = 5.4 Hz, 2H),4.04 (s, 3H). 54 4.34 545.2 1 ** * * DMSO δ 10.73 (s, 1H), 9.88 (t, J =5.5 Hz, 1H), 9.24 (d, J = 2.1 Hz, 1H), 8.88 (m, 1H), 8.84 (d, J = 1.9Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.28 (d, J= 8.0 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.83 (t, J = 7.8Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 4.73 (d, J = 5.7 Hz, 2H), 4.02 (s,3H), 2.79 (s, 3H). 55 4.65 536.0 1 ** * *** DMSO δ 10.82 (s, 1H), 9.88(12) (t, J = 5.8 Hz, 1H), 9.11 (s, 1H), 8.67 (m, 2H), 8.23 (m, 2H), 8.10(s, 1H), 7.87 (m, 2H), 7.44 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 3.7 Hz,1H), 4.85 (d, J = 5.7 Hz, 2H), 4.05 (s, 3H). 56 4.46 545.1 1 *** ** ***DMSO δ 10.69 (broad s, 1H), (13) (56) 9.83 (t, J = 5.3 Hz, 1H), 9.36 (s,1H), 9.28 (d, J = 2.1 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.80 (s, 1H),8.54 (t, J = 2.0 Hz, 1H), 8.20 (m, 3H), 7.79 (t, J = 7.8 Hz, 1H), 7.53(s, 1H), 4.71 (d, J = 5.4 Hz, 2H), 4.01 (s, 3H), 2.58 (s, 3H). 57 4.44548.1 1 *** ** ** DMSO δ 10.68 (broad s, 1H), (0.8) 9.21 (t, J = 5.1 Hz,1H), 9.13 (s, 1H), 8.80 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.20 (m,2H), 8.11 (d, J = 8.1 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.33 (d, J =2.1 Hz, 1H), 4.59 (d, J = 5.0 Hz, 2H), 4.03 (s, 3H), 3.71 (m, 2H), 2.54(s, 3H). 58 4.20 535.0 1 *** * ** DMSO δ 11.12 (broad s, 1H), (3.6) 9.90(t, J = 4.9 Hz, 1H), 9.34 (s, 1H), 9.27 (s, 1H), 8.91 (m, 3H), 8.49 (s,1H), 8.42 (s, 1H), 8.28 (m, 2H), 7.85 (t, J = 7.7 Hz, 1H), 7.53 (s, 1H),4.74 (d, J = 4.7 Hz, 2H). 59 4.89 562.1 1 * * * DMSO δ 10.58 (s, 1H),9.19 (t, J = 5.4 Hz, 1H), 9.05 (s, 1H), 8.90 (t, J = 1.7 Hz, 1H), 8.63(d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.15 (m, 3H), 8.07 (s, 1H), 7.75 (t,J = 7.8 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 5.37 (hept, J = 6.2 Hz, 1H),4.61 (m, 2H), 3.71 (m, 2H), 1.41 (d, J = 6.2 Hz, 6H). 60 5.32 573.11 * * * DMSO δ 10.70 (broad s, 1H), 9.87 (t, J = 5.9 Hz, 1H), 9.29 (d, J= 2.1 Hz, 1H), 8.87 (m, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.59 (s, 1H),8.46 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.14(s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 4.72 (d, J= 5.5 Hz, 2H), 4.00 (s, 3H), 3.32 (m, 1H), 1.40 (d, J = 6.9 Hz, 6H). 615.17 576.1 1 * * * DMSO δ 10.74 (s, 1H), 9.19 (t, J = 5.1 Hz, 1H), 8.89(m, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.47 (s, 1H), 8.15 (m, 3H), 8.05 (s,1H), 7.75 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 4.61 (m, 2H),4.04 (s, 3H), 3.71 (m, 2H), 3.22 (m, 1H), 1.34 (d, J = 6.9 Hz, 3H). 624.14 530.0 1 ** * *** DMSO δ 10.62 (broad s, 1H), (31) 9.84 (t, J = 5.8Hz, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.81 (m, 1H), 8.78 (m, 2H), 8.58 (d,J = 2.3 Hz, 1H), 8.39 (t, J = 2.2 Hz, 1H), 8.22 (m, 2H), 8.12 (s, 1H),7.80 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 4.9 Hz, 1H), 7.37 (d, J = 2.2 Hz,1H), 4.68 (d, J = 5.7 Hz, 2H), 4.00 (s, 3H). 63 4.19 548.0 1 *** * ***DMSO δ 10.64 (s, 1H), 9.52 (15) (47) (t, J = 5.9 Hz, 1H), 8.86 (d, J =2.2 Hz, 1H), 8.78 (m, 2H), 8.61 (d, J = 2.2 Hz, 1H), 8.44 (dd, J = 6.5,2.4 Hz, 1H), 8.37 (t, J = 2.2 Hz, 1H), 8.21 (m, 1H), 8.16 (s, 1H), 7.72(t, J = 9.4 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H),4.65 (d, J = 5.8 Hz, 2H), 4.00 (s, 3H). 64 3.37 539.2 1 * * ** DMSO δ10.61 (s, 1H), 9.37 (m, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 8.21 (m, 2H),7.89 (s, 1H), 7.80 (t, J = 7.8 Hz, 2H), 7.46 (s, 1H), 4.80 (d, J = 14.0Hz, 1H), 4.61 (d, J = 12.3 Hz, 1H), 4.01 (m, 4H), 3.64 (m, 2H), 3.42 (m,2H), 3.25 (m, 1H), 3.12 (m, 1H). 65 5.24 548.1 1 ** * * DMSO δ 10.71 (s,1H), 9.89 (m, 1H), 9.23 (s, 1H), 8.94 (s, 1H), 8.66 (s, 1H), 8.23 (m,5H), 7.82 (m, 1H), 7.54 (m, 1H), 7.43 (s, 1H), 4.70 (d, J = 4.5 Hz, 2H),4.02 (s, 3H). 66 3.39 539.2 1 ** * *** DMSO δ 10.62 (broad s, 1H), (88)9.37 (t, J = 5.4 Hz, 1H), 8.84 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.20(d, J = 7.4 Hz, 2H), 7.88 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.46 (s,1H), 4.80 (d, J = 13.4 Hz, 1H), 4.61 (d, J = 13.7 Hz, 1H), 4.02 (m, 4H),3.65 (m, 2H), 3.42 (m, 2H), 3.24 (m, 1H), 3.11 (m, 1H). 67 5.02 549.1 1*** *** * DMSO δ 10.56 (s, 1H), 9.44 (0.5) (12) (t, J = 6.0 Hz, 1H),9.19 (d, J = 7.3 Hz, 1H), 8.54 (m, 2H), 8.24 (t, J = 7.7 Hz, 1H), 8.14(d, J = 2.1 Hz, 1H), 7.80 (m, 1H), 7.69 (t, J = 10.0 Hz, 1H), 7.62 (m,1H), 7.52 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.28 (d, J =7.5 Hz, 1H), 4.49 (d, J = 5.8 Hz, 2H), 3.97 (s, 3H). 68 4.99 550.1 1 ****** *** DMSO δ 10.79 (broad s, 1H), (2.5) (90) (28) 9.89 (t, J = 5.5 Hz,1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.36 (m, 1H), 8.26 (d, J = 7.8 Hz, 1H),8.19 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 3.7 Hz, 1H), 7.85 (t, J = 7.6 Hz,1H), 7.61 (s, 1H), 7.25 (d, J = 3.6 Hz, 1H), 4.83 (d, J = 4.8 Hz, 2H),4.05 (s, 3H), 2.60 (s, 3H). 69 4.53 520.0 1 ** * ** DMSO δ 10.60 (s,1H), 9.83 (t, J = 5.7 Hz, 1H), 9.05 (s, 1H), 8.99 (m, 1H), 8.64 (d, J =2.1 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.07(s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 3.5 Hz, 1H), 7.43 (d, J= 2.1 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H), 4.79 (d, J = 5.5 Hz, 3H), 4.02(s, 3H). 70 2.73 497.1 1 * * ** DMSO δ 10.49 (broad s, 1H), 9.26 (t, J =5.8 Hz, 1H), 8.84 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.18(m, 2H), 7.91 (t, J = 7.0 Hz, 1H), 7.79 (m, 2H), 7.51 (d, J = 2.2 Hz,1H), 3.98 (s, 3H), 3.66 (m, 2H), 3.45 (m, 2H), 1.85 (m, 2H). 71 3.85561.2 1 *** *** * DMSO-d6 δ 10.44 (s, 1H), (0.15) (25) 9.14 (t, J = 6.2Hz, 1H), 9.09 (d, J = 4.4 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.66 (d, J= 2.2 Hz, 1H), 8.60 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.09(m, 3H), 7.90 (d, J = 4.5 Hz, 1H), 7.68 (t, J = 10.1 Hz, 1H), 7.33 (t, J= 7.2 Hz, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.64 (m, 3H). 72 5.28 548.11 * * ** DMSO-d6 δ 10.71 (s, 1H), 9.92 (t, J = 5.8 Hz, 1H), 9.26 (s,1H), 8.94 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H),8.21 (m, 2H), 8.05 (s, 1H), 7.91 (m, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.58(m, 1H), 7.46 (d, J = 2.2 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 4.03 (s,3H). 73 5.13 560.0 1 * * *** DMSO-d6 δ 9.86 (t, J = 5.6 (45) Hz, 1H),9.04 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.63 (m, 1H), 8.22 (m, 1H), 8.20(m, 2H), 7.85 (m, 2H), 7.69 (d, J = 3.7 Hz, 1H), 7.32 (m, 2H), 4.78 (d,J = 5.7 Hz, 2H), 4.03 (s, 3H). 74 4.74 536.0 1 * ** DMSO-d6 δ 10.76 (s,1H), 9.86 (t, J = 5.7 Hz, 1H), 9.13 (s, 1H), 8.80 (m, 1H), 8.67 (d, J =2.1 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.23(d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.76 (d, J= 1.4 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 4.77 (d, J = 5.4 Hz, 2H), 4.04(s, 3H). 75 3.40 523.1 1 * * DMSO-d6 δ 10.16 (bs, 1H), 9.08 (d, J = 7.8Hz, 1H), 8.55 (m, 3H), 8.29 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.5 Hz,1H), 7.79 (t, J = 7.8 Hz, 1H), 7.71 (s, 1H), 6.83 (d, J = 2.2 Hz, 1H),4.47 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.98 (s, 3H), 3.43 (m, 1H),3.03 (m, 1H), 2.03 (m, 3H), 1.70 (m, 1H). 76 3.41 523.1 1 * ** DMSO-d6 δ10.16 (bs, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.56 (m, 3H), 8.31 (d, J = 7.6Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.71 (s,1H), 6.84 (d, J = 2.0 Hz, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 4.24 (m, 1H),3.99 (s, 3H), 3.42 (m, 1H), 3.02 (m, 1H), 2.01 (m, 3H), 1.70 (m, 1H). 774.82 536.1 1 ** * *** DMSO-d6 δ 10.76 (broad s, (17) 1H), 9.77 (t, J =5.5 Hz, 1H), 9.09 (s, 1H), 8.83 (s, 1H), 8.68 (s, 1H), 8.29 (d, J = 7.7Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.87 (t,J = 7.9 Hz, 2H), 7.82 (s, 1H), 7.39 (d, J = 1.8 Hz, 1H), 4.63 (d, J =5.5 Hz, 2H), 4.04 (s, 3H). 78 4.15 518.0 1 ** * ** DMSO-d6 δ 12.41 (s,1H), 10.61 (s, 1H), 9.83 (t, J = 5.9 Hz, 1H), 8.66 (s, 1H), 8.42 (s,1H), 8.22 (m, 3H), 7.86 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 3.6 Hz, 1H),7.50 (s, 1H), 7.39 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 6.86(s, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.01 (s, 3H). 79 4.66 537.0 1 ** * *DMSO-d6 δ 10.65 (broad s, 1H), 9.96 (t, J = 5.7 Hz, 1H), 9.14 (s, 1H),9.01 (s, 1H), 8.77 (s, 1H), 8.61 (s, 1H), 8.22 (m, 2H), 8.07 (s, 1H),7.81 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 5.02 (d, J = 5.5 Hz,2H), 4.02 (s, 3H). 80 4.26 535.0 1 ** * *** DMSO-d6 δ 10.72 (broad s,(15) 1H), 9.83 (t, J = 5.9 Hz, 1H), 8.64 (m, 3H), 8.22 (m, 2H), 8.05 (s,1H), 7.86 (t, J = 7.8 Hz, 1H), 7.64 (m, 2H), 7.39 (d, J = 2.2 Hz, 1H),7.20 (d, J = 3.6 Hz, 1H), 4.80 (d, J = 5.3 Hz, 2H), 4.03 (s, 3H). 813.74 513.1 1 ** * ** DMSO-d6 δ 12.44 (s, 1H), 10.41 (s, 1H), 9.77 (t, J= 5.4 Hz, 1H), 9.02 (s, 1H), 8.87 (s, 1H), 8.71 (s, 1H), 8.42 (m, 1H),8.32 (d, J = 4.9 Hz, 1H), 8.22 (m, 3H), 7.78 (t, J = 7.6 Hz, 1H), 7.57(s, 1H), 7.38 (d, J = 5.0 Hz, 1H), 6.68 (s, 1H), 4.70 (d, J = 5.0 Hz,2H), 3.97 (s, 3H). 82 4.84 554.0 1 *** * *** DMSO-d6 δ 10.83 (broad s,(57) (13) 1H), 9.51 (m, 1H), 9.12 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H),8.56 (dd, J = 6.4, 2.5 Hz, 1H), 8.27 (m, 1H), 8.11 (s, 1H), 7.87 (d, J =3.7 Hz, 1H), 7.79 (t, J = 9.5 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.24(d, J = 3.7 Hz, 1H), 4.86 (s, 2H), 4.05 (s, 3H). 83 3.40 537.1 1 * * **DMSO-d6 δ 10.61 (s, 1H), 9.40 (m, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 8.51(s, 1H), 8.19 (t, J = 7.0 Hz, 3H), 7.83 (s, 1H), 7.78 (t, J = 7.8 Hz,1H), 7.51 (s, 1H), 5.14 (d, J = 12.7 Hz, 1H), 4.69 (d, J = 13.0 Hz, 1H),3.99 (s, 3H), 3.42 (m, 1H), 3.23 (m, 2H), 2.98 (m, 1H), 1.97 (m, 1H),1.88 (m, 2H), 1.46 (m, 2H). 84 3.40 537.1 1 * * ** DMSO-d6 δ 10.62(broad s, 1H), 9.41 (t, J = 5.7 Hz, 1H), 8.91 (s, 1H), 8.63 (s, 1H),8.51 (d, J = 2.1 Hz, 1H), 8.19 (t, J = 7.5 Hz, 2H), 7.83 (s, 1H), 7.78(t, J = 7.8 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 5.15 (d, J = 13.3 Hz,1H), 4.69 (d, J = 13.2 Hz, 1H), 3.99 (s, 3H), 3.42 (m, 1H), 3.21 (m,2H), 2.99 (m, 1H), 1.98 (m, 1H), 1.88 (m, 2H), 1.48 (m, 2H). 85 4.22499.1 1 ** * * Methanol-d4 δ 8.84 (d, J = 7.3 Hz, 1H), 8.47 (m, 1H),8.38 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.10 (m, 2H), 7.97 (s, 1H), 7.74(m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.30 (m,1H), 7.22 (d, J = 7.3 Hz, 1H), 4.61 (s, 2H). 86 2.82 523.1 1 * * **DMSO-d6 δ 10.61 (broad s, 1H), 9.07 (d, J = 7.1 Hz, 1H), 8.69 (s, 1H),8.55 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.15(m, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.31 (d, J = 2.1 Hz,1H), 4.06 (m, 1H), 4.00 (s, 3H), 3.88 (m, 3H), 3.54 (m, 1H), 3.33 (m,1H), 2.78 (m, 1H), 2.18 (m, 1H), 1.74 (m, 1H). 87 2.82 523.1 1 * * **DMSO-d6 δ 10.61 (broad s, 1H), 9.07 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H),8.55 (d, J = 2.0 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.15(m, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.31 (d, J = 2.1 Hz,1H), 4.06 (m, 1H), 4.00 (s, 3H), 3.87 (m, 3H), 3.56 (m, 1H), 3.33 (m,1H), 2.79 (m, 1H), 2.18 (m, 1H), 1.74 (m, 1H). 88 4.82 550.0 1 ** * ***¹H NMR (300 MHz, DMSO- (69) d6) δ 10.82 (s, 1H), 9.84 (t, J = 5.7 Hz,1H), 9.09 (s, 1H), 8.68 (m, 1H), 8.65 (m, 1H), 8.25 (m, 2H), 8.09 (s,1H), 7.89 (t, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H),4.75 (d, J = 5.4 Hz, 2H), 4.05 (s, 3H), 2.30 (s, 3H). 89 3.95 531.11 * * * ¹H NMR (300 MHz, DMSO- d6) δ 10.45 (broad s, 1H), 9.43 (t, J =3.5 Hz, 1H), 9.30 (s, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.78 (m, 1H), 8.70(s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 2H), 7.80 (m,2H), 7.70 (t, J = 7.8 Hz, 1H), 4.47 (dd, J = 13.6, 2.4 Hz, 1H), 3.93 (s,3H), 3.89 (dd, J = 13.6, 4.3 Hz, 1H). 90 5.21 568.1 1 *** *** *** ¹H NMR(300 MHz, DMSO) δ (1.8) (56) (27) 10.80 (broad s, 1H), 9.58 (t, J = 5.2Hz, 1H), 9.18 (s, 1H), 8.48 (dd, J = 6.4, 2.5 Hz, 1H), 8.37 (s, 1H),8.32 (m, 1H), 7.93 (d, J = 3.7 Hz, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.73(d, J = 2.0 Hz, 1H), 7.24 (d, J = 3.7 Hz, 1H), 4.85 (d, J = 4.8 Hz, 2H),4.05 (s, 3H), 2.61 (s, 3H). 91 3.78 553.2 1 *** ** *** DMSO-d6 δ 10.55(s, 1H), (10) (47) 9.29 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.17 (m,2H), 7.79 (m, 1H), 7.56 (s, 1H), 4.77 (d, J = 13.6 Hz, 1H), 4.57 (d, J =12.6 Hz, 1H), 4.04 (s, 1H), 3.98 (s, 3H), 3.73 (broad s, 1H), 3.61 (m,1H), 3.46 (s, 2H), 3.16 (m, 3H), 2.43 (s, 3H). 92 5.46 562.1 1 *** * *DMSO-d6 δ 10.64 (s, 1H), (15) 9.85 (t, J = 5.9 Hz, 1H), 9.34 (s, 1H),8.84 (s, 1H), 8.24 (m, 2H), 8.09 (s, 1H), 7.93 (d, J = 9.6 Hz, 1H), 7.81(t, J = 7.8 Hz, 1H), 7.56 (m, 2H), 4.67 (d, J = 5.6 Hz, 2H), 4.02 (s,3H), 2.57 (s, 3H). 93 4.91 610.1 1 ** *** * DMSO-d6 δ 10.64 (s, 1H),(32) 9.16 (t, J = 6.1 Hz, 1H), 9.11 (s, 1H), 8.66 (d, J = 2.2 Hz, 2H),8.16 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.85 (d, J = 3.7 Hz, 1H), 7.58(d, J = 8.9 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H),4.89 (s, 2H), 4.44 (m, 2H), 4.04 (s, 3H), 3.79 (m, 2H), 3.29 (s, 3H). 942.98 537.2 1 *** * *** DMSO-d6 δ 10.57 (s, 1H), (26) (65) 9.06 (d, J =7.2 Hz, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.20 (m, 3H), 7.83 (t, J = 7.8Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 4.01 (s, 3H), 3.91 (d, J = 6.9 Hz,3H), 3.77 (dd, J = 21.3, 12.6 Hz, 1H), 3.59 (m, 1H), 3.23 (m, 1H), 2.80(s, 1H), 2.43 (s, 3H), 2.16 (s, 1H), 1.75 (dd, J = 12.3, 8.1 Hz, 1H). 955.26 624.3 1 *** * ** DMSO-d6 δ 10.64 (s, 1H), (20) 9.16 (s, 2H), 8.56(d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.90 (d, J= 3.7 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 3.7Hz, 1H), 4.86 (s, 2H), 4.42 (s, 2H), 4.04 (s, 3H), 3.79 (m, 2H), 3.29(s, 3H), 2.60 (s, 3H). 96 7.40 520.0 3 *** ** DMSO-d6 δ 9.75 (t, J = 6.2(8.8) Hz, 1H), 8.81 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.13 (m, 5H),7.98 (s, 1H), 7.80 (s, 1H), 7.74 (d, J = 4.4 Hz, 2H), 4.67 (d, J = 5.7Hz, 2H), 3.97 (s, 3H). 97 5.37 566.1 1 ** * *** DMSO-d6 δ 10.61 (s, 1H),(62) 9.26 (t, J = 6.0 Hz, 1H), 9.11 (s, 1H), 8.66 (m, 2H), 8.17 (d, J =9.2 Hz, 1H), 8.10 (s, 1H), 7.84 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 8.9Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 3.7 Hz, 1H), 4.85 (s,2H), 4.04 (s, 3H), 4.03 (s, 3H). 98 5.05 570.1 1 *** * *** DMSO-d6 δ10.90 (s, 1H), (37) (13) 9.73 (t, J = 5.9 Hz, 1H), 9.14 (s, 1H), 8.67(d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 8.6, 2.2Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 3.7 Hz,1H), 7.82 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 3.7 Hz, 1H), 4.86 (s, 2H),4.05 (s, 3H). 99 3.17 537.2 1 *** * *** DMSO-d6 δ 10.57 (s, 1H), (43)(53) 9.06 (d, J = 7.1 Hz, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 8.21 (m, 3H),7.83 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 4.01 (s, 3H), 3.91(d, J = 7.0 Hz, 3H), 3.77 (dd, J = 21.4, 12.3 Hz, 1H), 3.60 (m, 1H),3.27 (s, 1H), 2.81 (d, J = 6.3 Hz, 1H), 2.43 (s, 3H), 2.16 (s, 1H), 1.76(m, 1H). 100 5.11 580.0 1 *** * *** DMSO-d6 δ 10.61 (m, 1H), (3.3) (31)9.25 (t, J = 5.7 Hz, 1H), 9.16 (s, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.31(s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 3.6 Hz, 1H), 7.61 (s,1H), 7.50 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 3.5 Hz, 1H), 4.84 (s, 2H),4.04 (s, 3H), 4.02 (s, 3H), 2.60 (s, 3H). 101 4.80 549.1 1 *** * ***DMSO-d6 δ 10.69 (s, 1H), (26) (21) 9.83 (t, J = 6.0 Hz, 1H), 8.71 (d, J= 5.0 Hz, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.29 (dd, J = 10.1, 5.0 Hz,2H), 8.16 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.73 (d, J =5.0 Hz, 1H), 7.67 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.20(d, J = 3.7 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.04 (s, 3H), 2.62 (s,3H). 102 5.31 584.1 1 *** *** *** DMSO-d6 δ 10.84 (s, 1H), (0.1) (28)(9.5) 9.79 (t, J = 5.8 Hz, 1H), 9.19 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H),8.29 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 8.6, 2.3 Hz, 1H), 8.02 (d, J =2.1 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 3.7 Hz, 1H), 7.25(d, J = 3.7 Hz, 1H), 4.83 (s, 2H), 4.05 (s, 3H), 2.62 (s, 3H). R_(t)means retention time (in minutes), [M + H]⁺ means the protonated mass ofthe compound, method refers to the method used for (LC)MS. Biologicalactivity in PI3K alpha, PIM-1 and mTOR for certain examples isrepresented in Table 3 by semi-quantative results: IC50 >1 μM (*), IC50<100 nM (***), 100 nM < IC50 < 1 μM (**). Quantitative data is alsopresented, in parentheses, depicting the actual IC₅₀ values (nM) forrepresentative examples.

TABLE 4 Pharmacokinetic parameters for some selected compounds.Administration I.V P.O Parameter Dose AUC inf T½ Cl Vd MRT Dose C maxTmax AUC inf Example (mg/Kg) (h*ng/ml) last (L/h/Kg) (L/Kg) (h) (mg/Kg)F % (ng/ml) (h) (h*ng/ml) 3 5.00 23709.33 1.41 0.36 0.46 1.27 10.00101.00 12403.41 0.25 48082.44 10 5.00 9467.60 0.57 0.53 0.28 0.53 10.0039.94 3389.29 0.25 7563.83 16 5.00 23568.46 2.23 0.27 0.99 3.33 10.00123.00 4820.00 0.50 29157.84 22 5.00 66912.04 3.42 0.07 0.37 4.94 10.0033.50 14950.90 0.16 44830.22 33 5.00 9159.37 2.91 0.60 1.12 1.87 10.0048.08 1266.30 0.16 8808.30 31 5.00 8930.77 0.39 0.69 0.56 0.81 10.0034.00 1635.18 0.25 6083.27 39 1.00 4455.10 1.66 0.25 0.59 2.39 3.0026.79 962.27 0.50 3580.16 68 5.00 16596.24 3.15 0.04 0.49 10.89 10.0034.51 2929.00 0.25 57280.69 The parameters estimated are: area under thecurve (AUC); plasmatic half life of the product (t½); plasmaticclearance (Cl); volume of distribution (Vd); MRT (Mean residence time);bioavailability (F %); maximum plasma concentration after oraladministration (Cmax); and time at which the Cmax occurs (Tmax).

ABBREVIATIONS

-   DCM dichloromethane-   MeOH methanol-   THF tetrahydrofuran-   dba dibenzylideneacetone-   DMF dimethylformamide-   DME 1,2-dimethoxyethane-   DMSO dimethylsulfoxide-   dppf diphenylphosphinoferrocene-   EtOAc ethyl acetate-   BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate-   HOAt 1-hydroxy-7-azabenzotriazole-   PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate-   PyBroP bromotripyrrolidinophosphonium hexafluorophosphate-   DMAP 4-dimethylaminopyridine-   HATU O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium-   PdCl₂(dppf).DCM 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)    dichloride, dichloromethane-   DIPEA diisopropylethylamine-   TFA trifluoroacetic acid-   min minutes-   h hours-   RT room temperature-   eq equivalents-   nBuOH n-butanol-   mw microwave

The invention claimed is:
 1. A method of treatment of a cancer, byadministering to a patient suffering from, or susceptible to the cancer,wherein the cancer is selected from the group consisting of bladdercancer, breast cancer, colon cancer, liver cancer, lung cancer, ovarycancer, pancreatic cancer, stomach cancer, cervical cancer, prostatecancer, squamous cell carcinoma, glioblastoma, melanoma, colon-rectumcancer, oral cancer, B-cell lymphoma, T-cell-lymphoma, Hodgkin'slymphoma, non-Hodgkin's lymphoma, Burkett's lymphoma; hematopoietictumors of myeloid lineage, and tumors of the central and peripheralnervous system, which method comprises administration of atherapeutically effective amount of a compound of formula I:

wherein: ring A and ring B represent a fused bicyclic group of any oneof the following formulae:

wherein in formula IA: W^(1a) is CH, CF or N; W^(2a) is CH, CF or N;W^(3a) is CR^(4a) or N; W^(4a) is CR^(5a) or N; W^(5a) is CR^(6a) or N;in formula IB: W^(1b) is CH, CF or N; W^(2b) is CH, CF or N; W^(3b) isCR^(4b) or N; W^(4b) is C or N; W^(5b) is CR^(6b) or N; W^(6b) is C orN; W^(7b) is C or N, and wherein when W^(3b) represents N, W^(4b) andW^(6b) represent C and W^(5b) represents C or N, then R* is hydrogen (inall other cases R* is absent); in formula IC: W^(1c) is CH, CR^(t1), N,NR^(q1), O or S; W^(2c) is CH, CR^(t2), N, NR^(q2), O or S; W^(3c) is Cor N; W^(4c) is CR^(5c) or N; W^(5c) is CR^(6c) or N; W^(6C) is C or N;in formula ID: W^(1d) is CH, CR^(t3), N, NR^(q3), O or S; W^(2d) is CH,CR^(t4), N, NR^(q4), O or S; W^(3d) is C or N; W^(4d) is CR^(5d) or N;W^(5d) is C or N; W^(6d) is C or N; each R^(t1), R^(t2), R^(t3), andR^(t4) is independently selected from halo, C₁₋₃ alkyl or C₃ cycloalkyl,a 3- to 5-membered heterocycloalkyl group, —OR^(s1), —CN,—N(R^(s2))R^(s3), —S(O)_(w1) CH₃ or —C(O)CH₃; w1 represents 0, 1 or 2;each R^(s1), R^(s2) and R^(3s) independently represent hydrogen or C₁₋₂alkyl; each R^(q1), R^(q2), R^(q3) and R^(q4) is independently selectedfrom C₁₋₃ alkyl or C₃ cycloalkyl, a 3- to 5-membered heterocycloalkylgroup or —C(O)CH₃; each R¹, R^(2a), R^(2b), R^(2c), R³, R^(4a), R^(5a),R^(6a), R^(4b), R^(6b), R^(5c), R^(6c), and R^(5d) are independentlyselected from hydrogen or a substituent selected from halo, —CN,—C(O)N(R^(f1))R^(f2), —C(O)R^(f3), —N(R^(f4))R^(f5), —C(O)OR^(f6),—OR^(f7), —OC(O)—R^(f8), —S(O)_(w2)CH³, C₁₋₈ alkyl, C₃₋₈ cycloalkyl anda 3- to 8-membered heterocycloalkyl groups, which latter three groupsare optionally substituted by one or more substituents selected from ═Oand E¹; w2 represents 0, 1 or 2; R^(f1), R^(f2), R^(f4), R^(f5) andR^(f7) independently represent hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyloptionally substituted by one or more substituents selected from ═O andE²; or R^(f1) and R^(f2) and/or R^(f4) and R^(f5) may be linked togetherto form a 4- to 8- membered ring optionally substituted by one or moresubstituents selected from C₁₋₃ alkyl, C₃ cycloalkyl and halo; R^(f3),R^(f6) and R^(f8) independently represent C₁₋₆ alkyl or C₃₋₆ cycloalkyloptionally substituted by one or more substituents selected from ═O andE²; X represents a direct bond, —C(R^(a))(R^(b))—, —O—, —S—, —N(R^(c))—,—N(R^(d))C(O)—, —C(O)N(R^(e))—or —N(R^(f))—C(O)—N(R^(g))—; Y represents-arylene-, -heteroarylene- (which latter two groups are optionallysubstituted by one or more substituents selected from E³),-heterocycloalkylene- or —C₁₋₁₂alkylene- (which latter two groups areoptionally substituted by one or more substituents selected from ═O andE⁴); R^(N) represents hydrogen or C₁₋₆ alkyl optionally substituted byone or more substituents selected from ═O and E⁵; Z represents-(A^(x))₁₋₇-, wherein each A^(x) independently represents—C(R^(x1))(R^(x2))—, —N(R^(x3))—, —C(O)—, —O—, —S—, —S(O)— or —S(O)₂—;R^(x1), R^(x2) and R^(x3) each independently represent hydrogen or asubstituent selected from E_(x); each E_(x) independently representshalo, —C(O)R^(y1), —N(R^(y2))—C(O)—N(R^(y3))(R^(y4)), C₁₋₆ alkyl orheterocycloalkyl (both of which latter two groups are optionallysubstituted by one or more halo atoms); R^(y1), R^(y2), R^(y3) andR^(y4) each independently represent hydrogen or C₁₋₃ alkyl optionallysubstituted by one or more halo atoms; each R^(a), R^(b), R^(c), R^(d),R^(e), R^(f) and R^(g) independently represent hydrogen, C₁₋₆ alkyl orC₃₋₆ cycloalkyl optionally substituted by one or more halo atoms; eachE¹, E², E³, E⁴ and E⁵ independently represents, on each occasion whenused herein: (i) Q⁴; (ii) C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl orheterocycloalkyl, each of which is optionally substituted by one or moresubstituents selected from ═O and Q⁵; any two E¹, E², E³, E⁴ and/or E⁵groups, may be linked together to form a 3- to 12-membered ring,optionally containing one or more unsaturations, and which ring isoptionally substituted by one or more substituents selected from ═O andJ¹; each Q⁴ and Q⁵ independently represent, on each occasion when usedherein: halo, —CN, —N(R²⁰)R²¹, —OR²⁰, —C(═Y¹)—R²⁰, —C(═Y¹)—OR²⁰,—C(═Y¹)N(R²⁰)R²¹, —C(═Y¹)N(R²⁰)—O—R^(21a), —OC(═Y¹)—R²⁰, —OC(═Y¹)—OR²⁰,—OC(═Y¹)N(R²⁰)R²¹, —OS(O)₂OR²⁰, —OP(═Y¹)(OR²⁰)(OR²¹), —OP(OR²⁰)(OR²¹),—N(R²²)C(═Y¹)R²¹, —N(R²²)C(═Y¹)OR²¹, —N(R²²)C(═Y¹)N(R²⁰)R²¹, —NR²²S(O)₂R²⁰, —NR²²S(O)₂N(R²⁰)R²¹, —S(O)₂N(R²⁰)R²¹, —SC(═Y¹)R²⁰, —SC(═Y¹)OR²⁰,—SC(═Y¹)N(R²⁰)R²¹, —S(O)₂R²⁰, —SR²⁰, —S(O)R²⁰, —S(O)₂OR²⁰, C₁₋₆ alkyl,C₃₋₆ cycloalkyl or heterocycloalkyl (which latter three groups areoptionally substituted by one or more substituents selected from ═O andJ²); each Y¹ independently represents, on each occasion when usedherein, ═O, ═S, ═NR²³ or ═N—CN; each R^(21a) represents C₁₋₆ alkyl, C₃₋₆cycloalkyl or heterocycloalkyl (which latter three groups are optionallysubstituted by one or more substituents selected from J⁴ and ═O); eachR²⁰, R²¹, R²² and R²³ independently represent, on each occasion whenused herein, hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or heterocycloalkyl(which latter three groups are optionally substituted by one or moresubstituents selected from J⁴ and ═O); or any relevant pair of R²⁰, R²¹and R²², may be linked together to form a 4- to 20- membered ring,optionally containing one or more heteroatoms, optionally containing oneor more unsaturations, and which ring is optionally substituted by oneor more substituents selected from J⁶ and ═O; each J¹, J², J⁴ and J⁶independently represents, on each occasion when used herein: (i) Q⁷;(ii) C₁₋₆ alkyl, C₃₋₆ cycloalkyl or heterocycloalkyl, each of which isoptionally substituted by one or more substituents selected from ═O andQ⁸; each Q⁷ and Q⁸ independently represents, on each occasion when usedherein: halo, —CN, —N(R⁵⁰)R⁵¹, —OR⁵⁰, —C(═Y^(a))—R⁵⁰, —C(═Y^(a))—OR⁵⁰,—C(═Y^(a))N(R⁵⁰)R⁵¹, —N(R⁵²)C(═Y^(a))R⁵¹, —NR⁵²S(O)₂R⁵⁰,—S(O)₂N(R⁵⁰)R⁵¹, —N(R⁵²)—C(═Y^(a))—N(R⁵⁰)R⁵¹, —S(O)₂R⁵⁰, —SR⁵⁰,—S(O)R⁵⁰, C_(l-6) alkyl or C₃₋₆ cycloalkyl (optionally substituted byone or more fluoro atoms) or heterocycloalkyl (optionally substituted byone or more substituents selected from halo, —OR⁶⁰ and —N(R⁶¹)R⁶²); eachY^(a) independently represents, on each occasion when used herein, ═O,═S, ═NR⁵³ or ═N—CN; each R⁵⁰, R⁵¹, R⁵² and R⁵³ independently represents,on each occasion when used herein, hydrogen, C₁₋₆ alkyl, or C₃₋₆cycloalkyl optionally substituted by one or more substituents selectedfrom fluoro, —OR⁶⁰ and —N(R⁶¹)R⁶²; or any relevant pair of R⁵⁰, R⁵¹ andR⁵² may be linked together to form, a 3- to 8-membered ring, optionallycontaining one or more heteroatoms, optionally containing one or moreunsaturations, and which ring is optionally substituted by one or moresubstituents selected from ═O and C₁₋₃ alkyl; R⁶⁰, R⁶¹ and R⁶²independently represent hydrogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyloptionally substituted by one or more fluoro atoms; wherein anyheterocycloalkyl group may be selected from non-aromatic monocyclic andbicyclic heterocycloalkyl groups in which one to four of the atoms inthe ring system is a heteroatom selected from N, O or S, and in whichthe total number of atoms in the ring system is from five to ten,wherein the heterocycloalkyl group may be bridged, and wherein theheterocycloalkyl group may be saturated or unsaturated containing one ormore double and/or triple bonds, wherein any heteroaryl group may beselected from an aromatic group containing one to four heteroatom(s)selected from N, O or S, wherein the heteroaryl group comprises five toten atoms in the ring system, and wherein the heteroaryl group ismonocyclic, bicyclic or tricyclic, provided that at least one of therings is aromatic, and that when the heteroaryl group is bicyclic ortricyclic it is linked to the rest of the molecule via an aromatic ring,or a pharmaceutically acceptable salt thereof.
 2. A method as claimed inclaim 1, wherein the cancer is astrocytoma.
 3. A method as claimed inclaim 1, wherein the cancer is acute myelogenous leukemias.
 4. A methodas claimed in claim 1, wherein the cancer is non-small cell lung cancer.5. A method as claimed in claim 1, wherein the cancer is non-Hodgkin'slymphoma.
 6. A method as claimed in claim 1, wherein ring A and ring Brepresents a fused bicyclic group of the following structure (optionalsubstituents are not shown):


7. A method as claimed in claim 1, wherein Y represents arylene,heteroarylene, heterocycloalkylene or C₁₋₆alkylene, all of which groupsare optionally substituted by one of the following groups:


8. A method as claimed in claim 1, wherein X represents —N(R^(c))— or adirect bond; and/or Z represents —C(O)-[T¹]- or —C(O)N(R^(x3))-[T¹]-, inwhich T¹ represents —(CH₂)₀₋₄-T²- and T² represents a direct bond or—C(O)—N(H)—CH₂—.
 9. A method as claimed in claim 1, wherein the compoundis selected from the following: